Short Stature, Onychodysplasia, Facial Dysmorphism, And Hypotrichosis

A number sign (#) is used with this entry because of evidence that short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome) can be caused by homozygous mutation in the POC1A gene (614783) on chromosome 3p21.

Description

SOFT syndrome is characterized by severely short long bones, peculiar facies associated with paucity of hair, and nail anomalies. Growth retardation is evident on prenatal ultrasound as early as the second trimester of pregnancy, and affected individuals reach a final stature consistent with a height age of 6 years to 8 years. Relative macrocephaly is present during early childhood but head circumference is markedly low by adulthood. Psychomotor development is normal. Facial dysmorphism includes a long, triangular face with prominent nose and small ears, and affected individuals have an unusual high-pitched voice. Clinodactyly, brachydactyly, and hypoplastic distal phalanges and fingernails are present in association with postpubertal sparse and short hair. Typical skeletal findings include short and thick long bones with mild irregular metaphyseal changes, short femoral necks, and hypoplastic pelvis and sacrum. All long bones of the hand are short, with major delay of carpal ossification and cone-shaped epiphyses. Vertebral body ossification is also delayed (summary by Sarig et al., 2012).

Clinical Features

Turnpenny and Thwaites (1992) reported a 14-month-old girl, born of consanguineous parents, who had short stature of prenatal onset, rhizomelic limb shortness particularly affecting the upper limbs, and unusual face. Features included relative macrocephaly, frontal balding, midface hypoplasia, small nose, macrostomia with downturned corners of the mouth, gingival hypertrophy, and hypoplasia or absence of the clitoris. Skeletal x-rays showed a dome-shaped thorax with delayed ossification of the proximal humeral and femoral epiphyses; there were no gross modeling, metaphyseal, or epiphyseal defects, and no vertebral dyssegmentation. Gross motor development was delayed, with her first steps coming at 18 months of age, at which time she had normal fine motor development, vision, and hearing, and a vocabulary of approximately 15 words. Follow-up examination at 9 years of age by Shalev et al. (2012) revealed small hands with short rectangular fingers and hypoplastic fingernails, a triangular-shaped face with protruding forehead and relatively deep-set eyes, large nose, and pointy chin with retrognathia. She also had irregularly positioned and crowded teeth, with severe dental caries.

Shalev et al. (2012) studied 8 affected individuals with severe disproportionate short stature, 1 of whom had previously been described by Turnpenny and Thwaites (1992), from 2 unrelated consanguineous Israeli families of Arab Muslim ancestry. The adult height of the affected individuals was between 112 and 127 cm, and was due to pre- and postnatal growth retardation. At a young age, patients had short stature, a relatively large head, and a long triangular face; the phenotype evolved to one in which the head was relatively small and the mandible large and pointy. Affected individuals had normal cognitive abilities and lacked any neurologic deficits. Other typical features included prominent nose, voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, waddling gait, and sparse hair after puberty. Characteristic skeletal changes included short long bones, especially femurs and humeri, with mild metaphyseal changes and very short femoral necks. One affected male from each of the families developed type 2 diabetes mellitus in the third decade of life, and both were also diagnosed with oligo-azoospermia. In addition, a 23-year-old female from the first family had Tanner stage III secondary sexual characteristics, with infantile breasts and no axillary hair; extensive metabolic and endocrine evaluation was normal. Two affected individuals from the first pedigree and 1 from the second also had various dental anomalies, including cone-shaped, widely spaced teeth, missing teeth of the right maxilla, and irregularly positioned, crowded teeth with severe dental caries.

Shaheen et al. (2012) described affected children from 3 unrelated consanguineous Saudi families who had primordial dwarfism with a distinctive facial dysmorphism. In the first family, 2 sisters and their male cousin had profound growth deficiency, relative macrocephaly, and distinct facial features involving an elongated triangular face, high forehead, hypertelorism, depressed nasal bridge, broad upturned nose, long philtrum, and posteriorly rotated low-set ears. Psychomotor development was normal. In the second family, a 6-year-old boy had primordial dwarfism and severe global developmental delay, as well as facial dysmorphism bearing a striking resemblance to those in the first family. His features included high forehead, deep-set eyes, prominent columella, dolichocephaly, stubby fingers, and hypotonia. In the third family, a 2.75-year-old boy had primordial dwarfism, global developmental delay, and facial features similar to those of the patients from the first 2 families, as well as small hands and feet. Skeletal survey showed diffuse osteopenia, striking epiphyseal hypoplasia particularly in the proximal humerus and femur, 2-year bone age delay, and short and broad carpals, metacarpals, tarsals, and metatarsals.

Mapping

Sarig et al. (2012) studied 8 affected members of 2 consanguineous Israeli families of Arab Muslim origin, previously reported by Shalev et al. (2012), who had short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, which Sarig et al. (2012) designated 'SOFT' syndrome. Whole-genome homozygosity mapping revealed 2 chromosomal regions of homozygosity larger than 2 Mb, a 3.7-Mb interval at 4q11 and a 7.3-Mb interval at 3p21.1-p21.31. Fine mapping excluded the candidate locus on chromosome 4, and a maximum lod score of 3.91 was obtained at marker D3S3561. Haplotype analysis narrowed the critical region to a 2.156-Mb interval between markers D3S1573 and rs2279323 on chromosome 3p21.

Molecular Genetics

Shaheen et al. (2012) performed autozygome analysis on 2 sisters with primordial dwarfism from a consanguineous Saudi family but found no shared overlap with known autosomal recessive causes of this disorder. Exome sequencing and autozygome filtration revealed homozygosity for a nonsense mutation in the POC1A gene (R81X; 614783.0001). The authors sequenced POC1A in 2 affected boys from 2 more consanguineous Saudi families, found homozygosity for the R81X mutation in both, and confirmed that all affected individuals shared a common ancestral disease haplotype. The R81X mutation was not found in 194 Saudi exomes or in the Exome Variant Server.

In 8 affected members of 2 consanguineous Israeli families of Arab Muslim origin with short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, originally described by Shalev et al. (2012), Sarig et al. (2012) identified homozygosity for a missense mutation in the POC1A gene (L171P; 614783.0002) that segregated with disease in both families and was not found in 300 population-matched controls.