Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis.

Caffey disease is characterized by massive subperiosteal new bone formation (usually involving the diaphyses of the long bones as well as the ribs, mandible, scapulae, and clavicles) typically associated with fever, joint swelling, and pain in children, with onset between birth and five months and spontaneous resolution by age two years. Episodes of recurrence of the manifestations of Caffey disease have been reported multiple times in individuals with the classic infantile presentation. Limited follow-up information suggests that adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, short stature, and an increased risk for bone fractures and/or deformities.

Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features: Perinatal (severe): characterized by pulmonary insufficiency and hypercalcemia. Perinatal (benign): prenatal skeletal manifestations that slowly resolve into one of the milder forms. Infantile: onset between birth and age six months of clinical features of rickets without elevated serum alkaline phosphatase activity. Severe childhood (juvenile): variable presenting features progressing to rickets. Mild childhood: low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots. Adult: characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Odontohypophosphatasia: characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations.

The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).

Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features: Perinatal (severe): characterized by pulmonary insufficiency and hypercalcemia. Perinatal (benign): prenatal skeletal manifestations that slowly resolve into one of the milder forms. Infantile: onset between birth and age six months of clinical features of rickets without elevated serum alkaline phosphatase activity. Severe childhood (juvenile): variable presenting features progressing to rickets. Mild childhood: low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots. Adult: characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Odontohypophosphatasia: characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (summary by Muller et al., 2006). Amelogenesis imperfecta may also be present in some patients (Bardet et al., 2016). A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement. For a discussion of phenotypic and genetic heterogeneity of familial hypomagnesemia, see HOMG1 (602014).

Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.

Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and a discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).

Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are characterized by congenital skin changes including erythematous-to-violaceous, reticulated, net-like or marbled-appearing patches of skin that do not mostly or completely resolve with warming or any other acute intervention. Individuals with isolated CMTC have no other syndromic features, and skin lesions tend to fade or resolve. Those with classic CMTC may have accompanying hemihypoplasia with body asymmetry, skin atrophy or ulceration, other vascular malformations, and occasional ocular issues (early-onset glaucoma and/or peripheral retinal vascular attenuation) but do not have other malformations, dysmorphic features, or cognitive impairment. The most common location for the CMTC lesions is on the legs. An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb. In more than half of affected individuals, skin lesions will generally fade across a wide range in age (6 weeks to 26 years), most commonly in the first year of life, but may not resolve completely.

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). Patients with a clinical diagnosis of Beemer-Langer syndrome have been found to carry mutations in the IFT80 gene (611177); see SRTD2, 611263. For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

A rare, genetic, primary bone dysplasia disease characterized by usually moderate, postnatal short stature, progressive genu vara deformity, a waddling gait, and radiological signs of metaphyseal dysplasia (i.e. irregular, sclerotic and widened metaphyses), in the absence of biochemical abnormalities suggestive of rickets disease. Intermittent knee pain, lordosis, and delayed motor development may also occasionally be associated.

The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy (calcification of the tendons, ligaments, and joint capsules) associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported.

Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014). Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.

The Borochowitz-Cormier-Daire type of spondyloepimetaphyseal dysplasia (SEMDBCD) is a rare type of autosomal recessive short-limb short-trunk dwarfism. Affected individuals have significant short stature with pronounced leg bowing, lumbar lordosis, and a waddling gait (summary by Borochowitz et al., 2004 and Shyamasundar et al., 2020).

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is caused by a defect in vitamin D 25-hydroxylation (Molin et al., 2017). The major function of vitamin D is to maintain calcium and phosphate levels in the normal range to support metabolic functions, neuromuscular transmission, and bone mineralization. Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (summary by Liberman and Marx, 2001). Rickets can occur because of inadequate dietary intake or sun exposure or because of genetic disorders. Vitamin D3 (cholecalciferol) is taken in the diet or synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. For vitamin D to be active, it needs to be converted to its active form, 1,25-dihydroxyvitamin D3. Vitamin D is transported in the blood by the vitamin D binding protein (DBP; 139200) to the liver, where vitamin D 25-hydroxylase (CYP2R1; 608713) is the key enzyme for 25-hydroxylation. Vitamin D 25(OH)D3, the major circulating form of vitamin D, is then transported to the kidney, where 25(OH)D3 is hydroxylated at the position of carbon 1 of the A ring, resulting in the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (summary by Christakos et al., 2010).

X-linked recessive hypophosphatemic rickets (XLHRR) is a form of X-linked hypercalciuric nephrolithiasis, which comprises a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009.

Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.

Spondylometaepiphyseal dysplasia, short limb-hand type is an autosomal recessive disorder with clinical and radiologic features of disproportionate short stature, platyspondyly, abnormal epiphyses and metaphyses, shortening of the lower and upper limbs, short and broad fingers, and premature calcifications. The disorder is progressive with respect to the severity of the bowing of the lower limbs and the appearance of calcifications, with some patients being wheelchair-bound from age 11 years (Bargal et al., 2009).

Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006).

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).

A rare syndrome characterised by mesomelic shortening and bowing of the limbs, camptodactyly, skin dimpling and cleft palate with retrognathia and mandibular hypoplasia. It has been described in a brother and sister born to consanguineous parents. Transmission is autosomal recessive.

Tibial torsion (twisting of the tibia) can cause toeing in or out, depending on whether it is internal or external torsion. Although some degree of internal tibial torsion is present in almost all infants because of the intrauterine position, it usually corrects spontaneously. Persistence of internal tibial torsion may be inherited as an autosomal dominant trait (summary by Fitch, 1974).

Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. In 2 families, affected individuals also showed a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Thus, the disorder may be considered a tumor predisposition syndrome (summary by Camacho-Vanegas et al., 2012).

This form of brachyolmia, here designated brachyolmia type 4, is characterized by short-trunk stature with normal intelligence and facies. The radiographic features include rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones (summary by Miyake et al., 2012).

Any metaphyseal anadysplasia in which the cause of the disease is a mutation in the MMP9 gene.

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XII is an autosomal recessive form characterized by recurrent fractures, mild bone deformations, generalized osteoporosis, delayed teeth eruption, progressive hearing loss, no dentinogenesis imperfecta, and white sclerae (summary by Lapunzina et al., 2010).

Blount disease is a developmental condition characterized by disordered endochondral ossification of the medial part of the proximal tibial physis resulting in multiplanar deformities of the lower limb (review by Sabharwal, 2009).

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011).

Fanconi renotubular syndrome-3 (FRTS3) is an autosomal dominant disorder characterized by rickets, impaired growth, glucosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and low molecular weight proteinuria (summary by Klootwijk et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).

The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (Ritter et al., 2022).

Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor (summary by Akawi et al., 2016).

Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the CDC45 gene.

Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive disorder characterized by muscle stiffness (myotonia) and chondrodysplasia. Affected individuals usually present in childhood with permanent muscle stiffness or bone deformities. Common clinical features include mask-like facies (narrow palpebral fissures, blepharospasm, and pursed lips); permanent muscle stiffness with continuous skeletal muscle activity recorded on electromyography; dwarfism; pectus carinatum; kyphoscoliosis; bowing of long bones; and epiphyseal, metaphyseal, and hip dysplasia. The disorder is slowly progressive but does not appear to alter life span (summary by Stum et al., 2006).

Spondyloepimetaphyseal dysplasia of the Di Rocco type (SEMDDR) is characterized by short stature, joint pain, and genu varum, as well as SEMD involving primarily the hips but also affecting the wrists, hands, knees, and ankles. Patients also exhibit variable degrees of metaphyseal and spine involvement (Di Rocco et al., 2018).

Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).

Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700.

Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).

Osteogenesis imperfecta type XXIII (OI23) is a mild recessive form of OI, characterized by osteopenia with or without recurrent fractures, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regress after early childhood; osteopenia persists, but responds well to bisphosphonate (Tuysuz et al., 2023).