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.

Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderate-to-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract.

Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (Cohen, 1993). Cohen and Barone (1994) further tabulated the findings in the 3 types of Pfeiffer syndrome.

The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).

Schinzel-Giedion syndrome is a highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia (summary by Hoischen et al., 2010).

The Murk Jansen type of metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly, prominent upper face, and small mandible. Hypercalcemia and hypophosphatemia occur despite the lack of parathyroid abnormalities (summary by Cohen, 2002).

Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.

Lenz-Majewski hyperostotic dwarfism is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, and distal limb anomalies, particularly brachydactyly and symphalangism. Patients have multiple radiographic abnormalities due to progressive generalized hyperostosis that affects the cranium, vertebrae, and diaphyses of tubular bones, leading to severe growth retardation (summary by Sousa et al., 2014).

Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.

Phosphoribosylaminoimidazole carboxylase deficiency (PAICSD) is an autosomal recessive disorder characterized by multiple congenital anomalies and early neonatal death (Pelet et al., 2019).

SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).

Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014).

Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009). Some patients survive infancy (Simpson et al., 2009; Fradin et al., 2011).

Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death (summary by Przylepa et al., 1996).

Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.

Hypomandibular faciocranial syndrome consists of craniosynostosis, prominent eyes, deficient midface and zygomatic arches, short nose with anteverted nares, protruding lower face, minute oral aperture, persistent buccopharyngeal membrane, severe mandibular hypoplasia, and various extracephalic anomalies (summary by Gorlin et al., 2001).

MARCH is an autosomal recessive lethal congenital disorder characterized by severe hydranencephaly with almost complete absence of the cerebral hemispheres, which are replaced by fluid, relative preservation of the posterior fossa structures, and renal dysplasia or agenesis. Affected fetuses either die in utero or shortly after birth, and show arthrogryposis and features consistent with anhydramnios. Histologic examination of residual brain tissue shows multinucleated neurons resulting from impaired cytokinesis (summary by Frosk et al., 2017).

Craniodiaphyseal dysplasia (CDD) is a severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. Progressive bony encroachment upon cranial foramina leads to severe neurologic impairment in childhood (summary by Brueton and Winter, 1990). The sclerosis is so severe that the resulting facial distortion is referred to as 'leontiasis ossea' (leonine facies), and the bone deposition results in progressive stenosis of craniofacial foramina (summary by Kim et al., 2011).

An extremely rare syndrome with characteristics of radial ray hypoplasia, choanal atresia and convergent strabismus. It has been reported in a father and his two daughters. The radial ray involvement varies from absent radius, first metacarpal and thumb to hypoplastic thumb or triphalangeal thumb. Transmitted as an autosomal dominant trait.

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.

Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.

Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3; 617667) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.

Basilicata-Akhtar syndrome (MRXSBA) is characterized by global developmental delay apparent from infancy, feeding difficulties, hypotonia, and poor or absent speech. Most patients are able to walk, although they may have an unsteady gait or spasticity. Additional findings include dysmorphic facial features and mild distal skeletal anomalies. Males and females are similarly affected (summary by Basilicata et al., 2018).

Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.

The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by Naiki et al., 2012). Genetic Heterogeneity of IFAP Syndrome IFAP syndrome-2 (IFAP2; 619016) is caused by heterozygous mutation in the SREBF1 gene (184756) on chromosome 17p11.

Autosomal recessive primary microcephaly-30 (MCPH30) is characterized by small head circumference, poor overall growth, and global developmental delay with variably impaired intellectual development. Affected individuals have been reported to have variable additional congenital anomalies, including atrial septal defect, dysmorphic facial features, tracheal stenosis, and anomalies of the skin and teeth (Carvalhal et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) is an autosomal dominant disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. Additional features may include developmental delay, impaired intellectual development, and growth failure/retardation (summary by Cuvertino et al., 2020 and Baldridge et al., 2020).

Craniometadiaphyseal osteosclerosis with hip dysplasia (CMDOH) is characterized by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings include hip dysplasia, heart malformations, variable developmental delay, and hematologic anomalies including anemia and pancytopenia. Bone biopsy shows evidence of increased osteoblast and reduced osteoclast function at the growth plate resorption zone, resulting in coarse trabeculae (Terhal et al., 2023). For syndromes with overlapping features, see osteopetrosis, autosomal recessive (OPTB1; 259700) and dominant (OPTA1; 607634), and osteopathia with cranial sclerosis (OSCS; 300373).