Skeletal dysplasias are a heterogeneous group of disorders, which result in disproportionate short stature. The nomenclature of these disorders remains confusing. In an attempt to develop uniformity, an international nomenclature and classification was proposed in 1969 and then updated multiple times. In the 1992 revision, the classification was based on radiodiagnostic and morphologic criteria (Figure 1). In the 1997 revision, [1] the families of disorders were rearranged based on current etiopathogenetic information regarding the gene and/or protein defect in these disorders (Table 1). In the 2002 revision, the dysostoses were incorporated in the Nomenclature. All these revisions merely reflect the complexity of skeletal-genetic phenotypes. Over the recent years the accumulation of knowledge on genes and proteins responsible for genetic disorders of the skeleton has been unprecedented. A molecular-pathogenetic classification of skeletal dysplasias based on the structure and function of the causative gene and protein was recently proposed [2] (Table 2).

Definitions

Osteochondrodysplasias refer to abnormalities of cartilage or bone growth and development. They are divided into i) defects of growth of tubular bones and/or spine which are frequently referred to as chondrodysplasias, e.g., achondroplasia ii) disorganized development of cartilage and fibrous components of the skeleton iii) abnormalities of density or cortical diaphyseal structure and/or metaphyseal modeling (e.g., osteogenesis imperfecta).

Dysostoses refer to malformations of individual bones, single or in combination, and does not refer to a generalized disorder of the skeleton. Many disorders that were previously referred to as dysostoses are now listed with the osteochondrodysplasias, since they are due to mutations of genes associated with dysplasias; e.g. brachydactyly C, Hunter Thompson dysplasia and Grebe dysplasia.

Clinical Evaluation

The clinical evaluation should start with a complete medical history that includes previous growth points. Since skeletal dysplasias may become apparent at various ages, study of growth points since birth may help to narrow the differential diagnosis. The family history should include information about other affected family members and possible consanguinity. Parents should be examined for evidence of disproportionate stature or other evidence of a skeletal dysplasia. Physical examination should focus on anthropometric measurements. The osteochondrodysplasias are generalized disorders of the skeleton, which usually result in disproportionate short stature (Figure 2a and 2b). A disproportionate body habitus may not be readily appreciated unless anthropometric measurements (i.e., arm span, upper to lower segment ratios) are carefully obtained. This assessment may help to determine if the disproportionate shortening affects primarily the trunk or the limbs: the proximal (rhizomelic), middle (mesomelic) or distal segment (acromelic).

The U/L segment ratio can be calculated by measurement of the lower segment from the symphysis pubis to the floor at the inside of the heel. The upper segment is then obtained by subtracting the lower segment from the total height. The U/L ratio can then be calculated and the results compared to published established norms for age and sex. Measurement of arm span provides an assessment of trunk vs limb length. In normal individuals, the arm span is very close to the total height measurement.

Establishing the correct diagnosis

The next step in the evaluation of disproportionate short stature is to obtain a full set of skeletal radiographs including views of the skull, spine, pelvis, extremities, hands and feet. Attention should be paid to the specific parts of the skeleton that are involved, the location of the lesion within each bone (epiphysis, metaphysis, diaphysis) and the recognition of unique patterns of abnormal skeletal ossification. Review of radiographs taken at different ages or before and after puberty may be helpful, because the radiographic features of many of these disorders may change with age.

Histologic studies of the chondro-osseous tissue may reveal specific abnormalities. Based on histological findings, chondrodysplasias can be grouped into four categories (Table 3). Finally, the recent advances in the basic biology of skeletenogenesis have allowed a classification based on the genetic defect and genetic confirmation of many of the skeletal dysplasias [2] (Table 2).

Management

Effective management requires precise diagnosis, prompt recognition of skeletal and non-skeletal complications, appropriate orthopedic and rehabilitative care, psychosocial support and genetic counseling. Orthopedic management aims at maximizing mobility and correcting deformities. Additional medical therapies have developed in a small number of these disorders.

Given the large number of these disorders, this paper will emphasize those that are clinically more relevant given their frequency, therapeutics or the insights they provide on the pathogenesis of bone disease.

ACHONDROPLASIA GROUP

Achondroplasia

Phenotype: Achondroplasia is due to a defect of endochondral bone formation, which results in rhizomelic shortening of the limbs (Figures 2a and 2b) [3]. Final height averages 135cm in men, and 125cm in women. Growth curves for achondroplasia have been developed. The size of the vertebral bodies and the diameter of the posterior vertebral arches are also decreased. Lumbar gibbus is present in infancy, and is replaced later by prominent lumbar lordosis. The mean head circumference follows a curve above the 97% for normal individuals (Figure 5a and 5b). Additional facial features include frontal bossing, hypoplasia of the maxilla, and mandibular prognathism. The foramen magnum is also affected and decreased in size. Therefore, secondary communicating hydrocephalus may develop. Cranio-cervical compression, which may present with upper limb weakness, clonus, apnea or sudden infant death, can be a significant neurologic complication of the small foramen magnum [4-6]. Otherwise, life expectancy and mental development is normal. Additional features include recurrent otitis media and serous otitis, which lead to conductive hearing loss.

Hypochondroplasia

Phenotype: Hypochondroplasia has been described as a milder form of achondroplasia, which presents with short stature usually during the second to third year of life (Figure 6). The characteristic facial features of achondroplasia are absent, and both short stature and rhizomelia are less pronounced. Adult height is approximately 120 to 150cm. Common features include genu varum and mild lumbar lordosis [7].

Thanatotropic Dysplasia

Phenotype: This is a lethal type of skeletal dysplasia characterized by extreme shortening of the limbs, large bulging forehead with prominent eyes, small narrow thorax, which may result in respiratory problems, and congenital heart and CNS defects.

Genetics: Achondroplasia is the most common of osteochondrodysplasias, with a frequency of approximately 1:26,000. Although transmitted as an autosomal dominant disorder, 90% of cases represent new mutations. Achondroplasia is caused by mutations of the gene for fibroblast growth factor receptor 3 (FGFR3) located in the short arm of chromosome 4 [8,9]. Patients with thanatotropic dysplasia are homozygotes for the FGFR3 mutations, while patients with achondroplasia or hypochondroplasia are heterozygotes.

Treatment: Treatment is primarily supportive. Primarily care physicians should be alert to the possibility of neurological complications associated with achondroplasia. With regards to treatment of short stature with growth hormone, limited data indicate a modest increase of growth velocity after the first couple of years of growth hormone therapy. However, the concern about worsening of body proportions with this treatment remains.

MESOMELIC DYSPLASIAS

Leri-Weill dyschondrosteosis

Phenotype: This syndrome is characterized by short stature primarily caused by reduction in the middle segments of the distal limbs (mesomelia), and a characteristic abnormality of the forearm, called Madelung deformity (Figure 3). Madelung deformity is the defining feature of Leri-Weill dyschondrosteosis, and consist of shortening and bowing of the radius and distal hypoplasia and dorsal dislocation of the ulna leading to limited mobility of the wrist. The severity of Madelung deformity and other clinical signs vary considerably among patients with Leri-Weill syndrome, with an average height reduction of -2.3 SDS. Adult heights can range from 135cm to normal. Overall, the phenotype is more severe in females and increases in severity with age.[10]

Langer mesomelic dysplasia

Phenotype: This rare disorder is characterized by severe disproportionate short stature with mesomelic shortening of the limbs, hypoplasia of the mandible, ulnar deviation of the hands, distal tapering of the humeri, and hypoplastic fibula, radius and ulna (Figure 4).

Genetics: Both the Leri Weill syndrome and Langer dysplasia are associated with defects of the SHOX gene. The SHOX gene is located in the pseudo-autosomal region on the short arm of the X chromosome. The pseudo-autosomal region is the major area of homology located at the tips of the X and Y chromosomes, and contains genes which escape X inactivation. Two copies of the genes are required for normal activity. The SHOX gene, which encodes a protein that has been shown to act as a transcription factor, is a critical gene involved in growth determination.[11-13] In normal individuals, the SHOX gene is found in two copies. A defect in a single copy of the SHOX gene either by point mutation, deletion or chromosomal rearrangement, which is called haploinsufficiency, results in the short stature of a number of clinical syndromes, including Turner syndrome and Leri Weill dyschondrosteosis.[14] Defects in the SHOX gene have been implicated in the pathogenesis of idiopathic short stature,[15,16] a heterogeneous group of patients who have short stature for unknown reasons. Current studies suggest that SHOX mutations occur in approximately 1% of patients with idiopathic short stature. There is now a wealth of evidence that the Leri Weill Syndrome results from SHOX mutations and deletions which occur in a single copy of the gene. Homozygosity of SHOX gene defects, and, therefore, complete absence of any SHOX gene product results in the phenotype of Langer mesomelic dysplasia. In contrast, females with an extra X chromosome (47,XXX) have three copies of the SHOX gene and are taller than the normal 46 XX females. Therefore, it appears that height is directly related to SHOX gene dosage.

DYSPLASIAS WITH DECREASED BONE DENSITY

Osteogenesis imperfecta

Phenotype: Osteogenesis imperfecta is a clinically heterogeneous disorder, which is frequently classified as follows[17]: Type IA is characterized by grey- blue sclera, osteoporosis with mild to moderate skeletal fragility, joint laxity, normal dentition and premature hearing loss (Figure 7). Fractures typically commence when the child starts to stand, and increase in frequency after childbirth and with aging, especially after menopause. Type IB includes all the above features found in Type IA, but dentition is also affected. Patients with type II osteogenesis imperfecta manifest severe skeletal fragility, which results in multiple fractures since infancy and may lead to premature death from associated complications and respiratory problems related to thorax deformities. Patients with Type III disease also manifest severe osteoporosis, frequent fractures, progressive bone deformities, and dwarfism secondary to vertebral compression fractures, disruption of the growth plates and bone deformities. Progressive scoliosis and thoracic deformities may result in frequent pneumonias. Sclera is bluish at birth, but becomes progressively white in childhood. Hearing may also be impaired. Type IV has similar disease characteristics as type I, with the main difference being the color of the sclera, which is white in patients of the type IV. A final group, type V, was recently proposed by Glorieux to include patients with osteoporosis, and high frequency of hypertrophic calluses.[18]

Genetics: The mode of inheritance of osteogenesis imperfecta is autosomal dominant, although Type III can be transmitted as both autosomal dominant and autosomal recessive. Approximately 80 to 90% of patients with osteogenesis imperfecta carry mutations in one of the two Type I collagen genes, the COL1A1 or COL1A2 genes[19,20]. The etiologies of the remaining cases, in which no mutations have been identified, remain unclear. Individuals with Type IA osteoporosis imperfecta express only one normal copy of the COL1A1 gene because they have a functionless mutant COL1A1 allele. These individuals synthesize normal collagen but in decreased amounts.[21] Most of the babies with osteogenesis imperfecta Type II have expressed mutations of COL1A1 or COL1A2, which result in the production of abnormal Type I collagen that is being incorporated into the extracellular matrix where it impairs the structure and function of the tissue.[22]

Bone histology: Histomorphometric evaluation of bone biopsies showed decreased cortical width and cancellous bone volume. The degree of cancellous volume reduction may vary among the different types of osteogenesis imperfecta, and is attributed to the increased bone turnover in these patients compared to controls.[23]

Treatment: Until the use of bisphosphonates in osteogenesis imperfecta, orthopedic intervention and support were the mainstays of treatment. Bisphosphonates are potent inhibitors of bone resorption, and are used widely in the treatment of osteoporosis in adults. The pioneer work of Glorieux has shown that the bisphosphonate pamidronate, at the dosage of 7 to 10 mg/kg/year given as an intravenous infusion in cycles every 3 months, resulted in significant improvement of bone density, reduction in the frequency of fractures and relief of chronic bone pain.[24,25] Linear growth was better in patients treated with pamidronate compared to untreated controls. Intravenous pamidronate has also been used successfully in severely affected neonates.[26] The duration of treatment, the long-term safety, and the use of other bisphosphonates remain important issues for future research.

Growth hormone therapy was studied in patients with osteogenesis imperfecta, because of its anabolic effect on the bone, but did not result in clinically significant improvement in bone density.[27,28] Transplanted allogenic mesenchymal stromal cells or autografting of genetically modified bone marrow derived mesenchymal stromal cells are being considered and evaluated for the treatment of severe osteogenesis imperfecta.[29,30]

Idiopathic Juvenile Osteoporosis

Phenotype: This is a rare disease, which mainly affects children between the ages of 8 and 14. It runs an acute phase, which usually lasts 2 to 4 years and almost invariably remits spontaneously. During the acute phase, the child may sustain multiple vertebral compression fractures, and fractures of the long bones, particularly the metaphyses, that lead to back pain, deformity and difficulty in walking.[31] The cause of juvenile idiopathic osteoporosis is unknown, and the diagnosis is based on the exclusion of other causes of secondary osteoporosis (Table 3). Differentiation from mild cases of osteogenesis imperfecta may be difficult. Positive family history, affected dentition and blue sclera indicate osteogenesis imperfecta, however, these features may be absent in mild cases.

Histological studies are limited, and it is unclear if bone resorption or bone formation is primarily affected.[32,33]

Treatment: Bisphosphonates, calcitriol, calcitonin and fluoride have been tried, but the results are equivocal.[31]

INCREASED BONE DENSITY WITHOUT DISRUPTION OF BONE SHAPE

Osteopetroses

Phenotype: Osteopetroses are rare human genetic disorders characterized by a generalized increase in skeletal mass due to markedly decreased bone resorption (Figure 8). Four types of human osteopetrosis have been defined. The infantile malignant osteopetrosis is a lethal autosomal recessive disease, which leads to anemia, thrombocytopenia and extramedullary hematopoiesis secondary to crowding of the marrow cavity. A defect in macrophage killing of bacteria frequently leads to severe and overwhelming infection. Optic atrophy and blindness may result from progressive encroachment on the optic

foramina.[34] The autosomal Dominant Type II Osteopetrosis (ADO II) is the most frequent osteopetrosis (5.5/100,000) that presents with increased frequency of fractures.[35] The Autosomal Dominant Type I Osteopetrosis (ADO I) is extremely rare, and is characterized by osteocondensation throughout the skeleton, and thickening of the cranial vault. It is the only form of osteopetrosis that is not associated with increased incidence of fractures.[36] Finally, osteopetrosis with renal tubular acidosis presents with fractures and/or short stature, visual impairment and mental retardation in the first few years of life.

Genetics: Recent studies have shown the defect to be in the osteoclast function and not in osteoclast differentiation.[37] Infantile malignant osteopetrosis is genetically heterogenous, and in some cases is caused by mutations of the TCIRG1 gene. This gene is involved in the function of a vacuolar ATPase present in the lysosomal membranes of osteoclasts, and which is important in the acidification of hydroxyapatite and therefore in its resorption. The genes for autosomal dominant osteopetrosis have not yet been identified. Finally, the osteopetrosis with renal tubular acidosis is due to a defect in the gene encoding carbonic anhydrase type II.

Treatment: Malignant infantile osteopetrosis is lethal unless a successful bone marrow HLA matched donor transplantation is performed.[38] The present data show a 50% survival with a median of 15 months post transplantation. Treatment with interferon gamma has been shown to give some promising results in some patients. Neurosurgical unroofing of the optic foramina may ameliorate the visual disability.

Pyknodysostosis

It is an autosomal recessive osteochondrodysplasia in which patients have short stature, dysmorphic features, osteosclerosis and frequent fractures. As in osteopetrosis there is evidence of decreased bone resorption. These patients have found to have mutations of the cathepsin K gene, which is a lysosomal protein responsible for the proteolytic degradation of the osteoclast.[39]

DISORDERS OF MINERALIZATION

Hypophosphatasia

Phenotype: Hypophosphatasia is an inherited disease characterized by defective bone mineralization, and a deficiency of tissue-non-specific alkaline phosphatase (TNSALP) activity [40]. The disease presents with short stature, bowing of the legs, and is highly variable in clinical expression, ranging from stillbirth without mineralized bone to pathologic fractures which develop only late in adulthood. Depending on the age at diagnosis, five clinical forms are currently recognized: perinatal (lethal), infantile, childhood, adult and odontohypophosphatasia. In some cases, differential diagnosis from osteogenesis imperfecta may be difficult, because of overlap in clinical and biochemical data. Laboratory findings include decreased serum alkaline phosphatase, elevated serum and urine phosphoethanolamode, radiologic evidence of metaphyseal fraying and decreased bone mass.

Genetics: Hypophosphatemia is due to mutations in the alkaline phosphatase liver type gene, also named the TNSALP gene, localized on chromosome 1p36.1-34 [41]. The majority of the mutations are missense mutations, which result in variable residual enzymatic activity, and may explain the great variability of the phenotype. The disease is inherited as an autosomal recessive trait, although in the milder forms of childhood and adult onset both autosomal dominant and recessive inheritance have been described.

Treatment: Genetic counseling and prenatal diagnosis by determination of the TNSALP gene mutations in chorionic villus cells.

Hypophosphatemic rickets

Background - Phosphate homeostasis: Similar to calcium, the serum phosphate level is maintained within a narrow range. The principal organ that regulates phosphate homeostasis is the kidney. Serum inorganic phosphorus is filtered by the glomerulus, and 80% of the filtered load is reabsorbed predominately along the proximal nephron. Regulation of the proximal renal tubular reabsorption is achieved through regulation of the brush border membrane type IIa sodium phosphate co-transporter (NPT2). Parathyroid hormone (PTH) is the best characterized physiological regulator of phosphate reabsorption, but its principal function is to maintain calcium homeostasis. PTH increases urinary phosphate excretion via inhibition of NPT2 expression. In addition, hypophosphatemia stimulates calcitriol synthesis via the 25(OH)D-1a-hydroxylase in the kidney, leading to increased intestinal calcium and phosphate absorption and enhanced mobilization of calcium and phosphorus from bone. The resultant increase in serum calcium concentrations inhibits PTH release, with a subsequent increase in urinary calcium excretion and increase in renal tubular phosphate reabsorption.

Phenotype: X-linked hypophosphatemic rickets accounts for 80% of cases of familial phosphate wasting, and is, therefore, the most common inherited hypophosphatemic disorder. Clinically, X-linked hypophosphatemic rickets may present at around 6 months with frontal bossing and mild bowing of the lower limbs. Impaired growth and progressive worsening of the leg bowing may be observed by 12 months, as the infant begins to walk. In the absence of treatment, affected children show poor statural growth and progressive deformity of the legs, leading to abnormal gait. Dentition may be late, and poor dental development may be associated with spontaneous dental abscesses. In adults, the lower limb deformities cause arthralgias and arthritis. Ectopic calcification of the spinal ligaments and the Achilles tendon is a common late complication. Muscle weakness, a major feature of vitamin D deficiency and phospate deprivation, is strikingly absent. Phenotype is frequently more severe in affected males compared to females, in whom the findings of the disease may be much more variable and limited only to low serum phosphate levels.

Biochemical findings: Hypophosphatemia occurs as a result of decreased renal tubular phosphate reabsorption. Serum calcitriol levels are reduced or inappropriately normal for the degree of hypophosphatemia, while calcium and PTH levels are normal. Aberrant regulation of 25(OH)D-1-?-hydroxylase accounts for the low or inappropriately normal levels of calcitriol in the face of hypophosphatemia.

Management: Oral supplementation with phosphate combined with vitamin D is effective in correcting hypophosphatemia, improving growth and reducing leg deformities [42-44]. Phosphate therapy must be given in five divided doses, while the most effective vitamin D replacement is calcitriol. Close monitoring of biochemical parameters is necessary to avoid hypercalcemia and hypercalciuria. Nephrocalcinosis is therefore a common complication of treatment, and renal ultrasounds are recommended on an annual basis. Renal impairment, however, is rare. Finally, orthopedic care and surgical correction of limb deformities, especially during puberty, are part of an effective treatment plan.

Autosomal hypophosphatemic rickets

Phenotype: This disorder is characterized by low serum phosphorous concentrations and phosphaturia, due to impaired renal tubular renal reabsorption of phosphorus, associated with inappropriately low or normal 1, 25 (OH)2D levels. These biochemical abnormalities result in rickets and osteomalacia. The childhood onset is phenotypically similar to X-linked hypophosphatemic rickets. The adult form presents with osteomalacia and bone pain, fractures, muscle weakness, but no bone deformities [45].

Hereditary hypophosphatemic rickets with hypercalciuria

Phenotype. Patients with this disorder present with osteomalacia, bone pain, rickets, muscle weakness and growth retardation [46]. The biochemical characteristics of the syndrome are hypophosphatemia and phosphaturia secondary to decrease renal reabsorption of phosphate, and elevated levels of calcitriol, which account for the hypercalciuria. PTH levels are not elevated, suggesting that the increased calcitriol concentrations represent a normal response to hypophosphatemia.

Genetics of hypophosphatemic rickets: The study of inherited hypophosphatemic disorders has led to the discovery of new regulators of phosphate homeostasis [47]. X- linked hypophosphatemic rickets is caused by mutations of the PHEX gene (initially called PEX), which is located on chromosome Xp22.1 and encodes a M13 metalloprotease, whose native substrate has not yet been identified. How the loss of PHEX function leads to renal phosphate wasting, defective bone mineralization and reduced calcitriol synthesis is not yet apparent. Recent studies suggest that PHEX regulates the proteolysis of a circulating humoral factor, and that the fibroblast growth factor (FGF)-23 is possibly the humoral factor in question [47,48]. Activating mutations of the FGF-23 have been identified in kindreds with autosomal hypophosphatemic rickets, indicating that FGF-23 plays a central role in the pathophysiology of these disorders [49]. Finally, defects of the major renal tubular phosphate transporter, NPT2, have been proposed as the cause of the hereditary hypophosphatemic rickets with hypercalciuria, but no mutations have thus far been identified in affected kindreds [50].

The vitamin D system

Background - the metabolism and action of vitamin D: Vitamin D is formed in the skin by photocatalysis. The vitamin D (cholecalciferol) pathway includes an initial hydroxylation in the liver by the 25-hydroxylase and further 1?-hydroxylation to calcitriol in the renal mitochondria under tight PTH regulation. Vitamin D metabolites, ans primarily calcitriol, lead to calcium absorption by the gut and have direct biologic effects on osteocytes.

Vitamin D dependent rickets type I (deficiency of the 1?-hydroxylase)

Phenotype: Clinical symptoms are similar to vitamin D deficiency, which progressively worsen if diagnosis and treatment are delayed. Symptoms are those of rickets, and include failure to thrive, hypotonia, deformities of the spine and long bones (bowing of legs), as well as generalized muscle weakness and growth retardation. Additional features include a wide frontal fontanelle, frontal bossing, craniotabes, enamel hypoplasia, rachitic rosary and widening of metaphyseal areas as evidenced by enlargement of wrists and ankles.

Diagnosis: Hypocalcemia may occur before any radiological findings of rickets and may result in convulsions. Hypocalcemia leads to secondary hyperparathyroidism and hypophosphatemia.

Genetics: Vitamin D dependent rickets type I is caused by deficiency of the 1a-hydroxylase gene. It is transmitted as an autosomal recessive disorder [51,52].

Management: The treatment of choice is life long replacement with 1,25 (OH)2D3, initially at the dosage of 1 to 2 µg daily, followed by a maintenance dose of 0.5 to 1 ug daily. Such treatment corrects biochemical abnormalities and results in rapid and complete resolution of clinical symptoms. Adequate calcium supplementation during the initial bone-healing phase is important. Regular monitoring of calcium excretion to avoid hypercalciuria and calcium deposition in the kidney is recommended.

Hereditary vitamin D resistant rickets

Phenotype: Clinical manifestation is similar to rickets [53]. In addition, many patients have partial or complete alopecia.

Genetics: In the majority of cases, the disease is caused by mutations in the vitamin D receptor.

Treatment: The disease is resistant to even high doses of vitamin D but is responsive to intravenous or oral calcium.

DISORDERS OF PARATHYROID HORMONE ACTION

Jensen's metaphyseal chondrodysplasia

Phenotype: This is a rare form of short limb dwarfism secondary to severe growth plate abnormalities. Dysmorphic features at birth may be variable, and include micrognathia, hypertelorism, high skull vault, wide cranial sutures and high arched palate. Choanal atresia and/or rib fractures may result in postpartum respiratory distress. Severe disproportionate short stature with bowing of the legs, waddling gait and short lower extremities compared to the relative long arms become more obvious as the child grows.

Diagnosis: Biochemical findings are similar to hyperparathyroidism, with asymptomatic hypercalcemia and hypophosphatemia, which persist throughout life, and low or undetectable concentrations of PTH and PTHrP [54]. Radiographic findings change throughout life. In infancy, findings include marked rickets-like metaphyseal changes and radiographic findings as seen in hyperparathyroidism (i.e. loss of normal cortical outline, subperiosteal bone resorption and generalized osteopenia). Rachetiform deformities gradually disappear and irregular patches of partially calcified cartilage start protruding into the diaphyses during childhood, which gradually disappear during adolescence, giving way to a more normal trabecular pattern during adulthood. However, the ends of the tubular bones remain enlarged and expanded [55,56].

Genetics: Activating mutations of the receptor of PTH/PTHrP are shown to cause Jansen's metaphyseal chondrodysplasia [57]. Identification of the molecular defect of this rare disorder provides important new insight on the role of PTH/PTHrP receptor on skeletal development. It appears that both PTH and PTHrP stimulate the proliferation of chondrocytes in growth plates, inhibit the differentiation of these cells into hypertrophic chondrocytes and inhibit mineralization. Inheritance of Jansen's dyplasia is autosomal dominant, generally without a positive family history suggestive of spontaneous mutation.

Pseudohypoparathyroidism

Phenotype: The term describes a group of conditions in which there is a variable degree of resistance to PTH and a characteristic clinical phenotype of disproportionate short stature, with selective distal shortening of tubular bones, predominantly of metacarpals but also of metatarsals and phalanges, round face, and obesity. The best characterized form of the disorder is known as Type Ia, and includes the combinations of the above described clinical features with complete resistance to PTH. In addition there is high frequency of mental retardation (mean IQ in the range of 60) and ectopic subcutaneous or intracranial calcifications [58]. In many instances there is tissue resistance to the effects of other biological hormones, e.g., thyroid hormone or gonadotropins. Type Ib refers to the presence of PTH resistance without skeletal features. Finally, in pseudo-pseudohypoparathyroidism, the somatic features of pseudohypoparathyroidism occur in the present of normal serum chemistries and normal response to PTH.

Diagnosis: Biochemical findings include hypocalcemia, which may result in seizures or tetanic episodes, and hyperphosphatemia in the face of elevated serum PTH concentrations.

Genetics: The PTH receptor belongs to the G-protein-coupled family receptors. Pseudohypoparathyroidism Ia is caused by a defect in the a subunit of the stimulatory G- protein (GNAS1). GNAS1 is imprinted in a tissue-specific manner in humans, and renal expression of GNAS1 appears to be determined by the maternal allele. Family studies indicate that maternal transmission of the mutation in GNAS1 results in pseudohypoparathyroidism Ia [59]. Pseudopseudohypoparathyroidism is caused by paternal transmission of a mutated GNAS1 gene; in such cases, the normal maternal allele results in normal renal responsiveness to PTH. To date, no mutations in the GNAS1 have been identified in the patients with pseudohypoparathyroidism Ib. Finally, a variant of pseudohypoparathyroidism Ia associated with precocious male puberty has been attributed to a temperature-sensitive Gsa protein. This unstable protein functions poorly at body temperature in most tissues, but is stable at 32oC, and therefore, permits testicular function [60].

Management: The aim of treatment is to normalize serum calcium levels with calcium (50-100 mg/kg day of elemental calcium) and vitamin D supplementation. Calcitriol is the vitamin D replacement of choice. Serum calcium levels are maintained at the low normal range.

I wish to express my appreciation to Brian Betensky for his editorial assistance in the preparation of this chapter.