Short Syndrome

A number sign (#) is used with this entry because of evidence that SHORT syndrome can be caused by heterozygous mutation in the PIK3R1 gene (171833) on chromosome 5q13.

Description

'Short,' the mnemonic designation for this syndrome, is an acronym: S = stature; H = hyperextensibility of joints or hernia (inguinal) or both; O = ocular depression; R = Rieger anomaly; T = teething delay. The name was given by Gorlin (1975), who described the syndrome in 2 brothers.

Dyment et al. (2013) noted that the features listed in the acronym for SHORT syndrome do not capture the full range of the clinical phenotype, which can include a recognizable facial gestalt consisting of triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella, as well as near-universal partial lipodystrophy, insulin resistance, nephrocalcinosis, and hearing deficits. Notably, both developmental milestones and cognition are normal for individuals with SHORT syndrome.

Clinical Features

Sensenbrenner et al. (1975) described a 6-year-old girl with Rieger anomaly, short stature, and partial lipodystrophy of the face and upper limbs. She also had delayed dental eruption, delayed bone age, and hyperextensibility of the joints. Gorlin (1975) reported the same condition in 2 brothers, aged 11 and 4 years. Gorlin (1975) suggested autosomal recessive inheritance because of possible consanguinity in 1 set of parents.

Aarskog et al. (1983) described a family from the Lofoten Islands of Norway in which 4 persons in 3 generations had nonprogressive lipodystrophy present from infancy affecting primarily the face and buttocks. Affected persons also had the Rieger anomaly, midface hypoplasia, retarded bone age, and hypotrichosis. Of 2 sisters, 1 had glucose intolerance at age 55 years, and the other had insulinopenic diabetes mellitus at age 39 years. Aarskog et al. (1983) suggested that the disorder in their family was distinct from SHORT syndrome because of the absence of joint hypermobility and less extensive lipodystrophy in their patients.

Toriello et al. (1985) reported a patient with SHORT syndrome characterized by lipoatrophy, delayed speech development, clinodactyly, and short stature. The boy also had deafness, which the authors noted had not previously been reported in the SHORT syndrome. Stratton et al. (1989) reported a brother and sister with short stature, delayed bone age, developmental delay, congenital hip dislocation, and iridocorneal abnormalities with onset of glaucoma at or soon after birth. Many of the features resembled those of the SHORT syndrome, but triangular face and lipoatrophy were not present.

Schwingshandl et al. (1993) described a girl with most of the typical features of SHORT syndrome who, at age 14 years, developed nonketotic hyperglycemia. At the age of 16.5 years, diabetes mellitus with severe insulin resistance was diagnosed. From an early age, the patient had had partial lipodystrophy, as well as megalocornea and a peculiar progeria-like face. At age 6 years, bilateral sensorineural hearing loss was detected.

Verge et al. (1994) also described insulin-resistant diabetes in SHORT syndrome. They suggested that defective function of insulin receptors in adipose tissue may explain the paucity of fat storage in this disorder.

Bankier et al. (1995) described the association of triangular face, deep-set eyes, micrognathia, small facial bones, and narrow body build in 3 members of an English family and in an unrelated Australian girl. Absence of iridal stroma was found in the Australian girl and in the English mother; the son of the English woman also had sensorineural deafness. Bankier et al. (1995) noted that the symptom complex was similar to the SHORT syndrome, although all 4 patients had low-normal height and did not manifest joint hyperextensibility. Reardon and Temple (2008) reported that 1 of the female patients reported by Bankier et al. (1995) developed nephrocalcinosis as an adult. The affected son of this patient, who was diagnosed with SHORT syndrome in the neonatal period, had nephrocalcinosis and increased serum and urinary calcium at 2 months of age.

Sorge et al. (1996) described a 9-year-old Italian boy with short stature, partial lipodystrophy, minor facial anomalies, mild hyperextensibility of joints, ocular depression, Rieger anomaly, and delay in speech development and dental eruption. Because the father and sister showed a striking similarity to the propositus, Sorge et al. (1996) suggested an autosomal dominant gene with variable expression in this family. The sister had bilateral and symmetrical lens opacities, a feature that had not been reported previously in affected subjects or their relatives. Sorge et al. (1996) suggested that the disorder reported by Aarskog et al. (1983) was the same disorder.

Brodsky et al. (1996) added congenital glaucoma as a feature of the SHORT syndrome. Their patient was a 9-year-old boy who had enlarged cloudy corneas, Rieger anomaly, and elevated intraocular pressure at birth. He also had bilateral sensorineural hearing loss, short stature, and mild developmental delay. The face had a triangular configuration with prominent forehead, deeply set eyes, thin nasal alae, and a proportionately small middle and lower face. The face and chest showed diminished subcutaneous fat, and the hands had thin, dry, wrinkled skin, producing a progeroid appearance. A paternal uncle reportedly had a similar appearance.

Koenig et al. (2003) described a mother and son with short stature, progeroid facies, Rieger anomaly, teething delay, mild developmental retardation, particularly speech delay, and a slight build with lack of subcutaneous fat. Resistance to insulin was suggested by an oral glucose tolerance test in the mother, whereas the test was normal in the son at the age of 2 years. After reviewing the reported cases of SHORT syndrome, Koenig et al. (2003) concluded that 5 familial cases in different generations, equally affected male and female patients, and male-to-male transmission support autosomal dominant inheritance, possibly with germline mosaicism in the cases of affected sibs and unaffected parents.

Reardon and Temple (2008) reported 3 patients, including a mother and son previously reported by Bankier et al. (1995), with a clinical diagnosis of SHORT syndrome who all developed nephrocalcinosis. Two of the patients had nephrocalcinosis in infancy and also showed increased serum and urinary calcium. Reardon and Temple (2008) postulated that disordered calcium metabolism may be a previously unreported feature of SHORT syndrome.

Reis et al. (2011) studied a 6-year-old Caucasian girl with a diagnosis of SHORT syndrome, whose ocular features included Rieger anomaly, congenital glaucoma, microcornea, and nystagmus. She had short stature, poor weight gain, and macrocephaly, as well as hyperextensible joints, delayed eruption of teeth, decreased subcutaneous fat in the upper trunk and head, and dysmorphic facial features including prominent forehead, sunken eyes, small chin, and hypoplastic nares. Her hearing was normal, hands and feet were small with normal structure, and umbilicus was described as 'a bit pouchy' with mildly increased skin. Brain MRI showed normal structures.

Avila et al. (2016) reviewed the clinical features of 32 individuals, including 8 newly ascertained patients, with genetically confirmed SHORT syndrome. The major features described in the SHORT acronym were not universally seen, and only half (52%) had 4 or more of the classic features. The most common features included intrauterine and postnatal growth restriction, lipoatrophy, and a characteristic facial gestalt characterized by a progeroid appearance with prominent forehead, triangular face, deep-set eyes, hypoplastic alae nasi, midface hypoplasia, small chin, low-set ears, and downturned mouth. Hyperextensible joints or inguinal hernia was found in only 10 of 29 cases, and Rieger anomaly was only found in 13 of 30 cases, although some patients had other anterior chamber defects. Insulin resistance was found in 13 of 17 patients, and diabetes was found in 9 of 14. Three patients had cardiac anomalies and 5 had sensorineural deafness. Avila et al. (2016) concluded that cardinal features of the disorder warranting monitoring include lipoatrophy and insulin resistance, and that minor features of SHORT syndrome should include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints, and inguinal hernia.

Cytogenetics

In a mother with Rieger syndrome (180500) and polycystic ovaries (see 184700) and a son manifesting SHORT syndrome, Karadeniz et al. (2004) identified a t(1;4)(q31.2;q25) translocation. Because Rieger syndrome can be caused by mutation in the PITX2 gene (601542) on chromosome 4q25, Karadeniz et al. (2004) suggested that the 2 syndromes may represent a single condition reflecting variable expression of this gene.

In a 6-year-old Caucasian girl with the complete constellation of features comprising SHORT syndrome, in whom screening of PITX2 showed normal sequence and copy number, Reis et al. (2011) identified heterozygosity for a 2.263-Mb deletion on chromosome 14q22.1-q22.2, encompassing BMP4 (112262) and 13 other genes. The minimum deleted interval was chr14:51,402,258-53,665,008 and the maximum interval was chr14:51,400,039-53,667,259 (NCBI36). Quantitative PCR confirmed deletion of 1 copy of BMP4 and the presence of both copies of the OTX2 gene (600037). The patient's mother, who had high myopia but otherwise normal ocular and systemic features, showed no evidence of BMP4 deletion; the unaffected father was unavailable for testing. Reis et al. (2011) suggested that SHORT syndrome might be a contiguous gene deletion syndrome requiring deletion of 1 or more other genes in addition to BMP4.

Molecular Genetics

By whole-exome sequencing in 2 unrelated patients with SHORT syndrome, Thauvin-Robinet et al. (2013) identified de novo mutations in the PIK3R1 gene (171833.0002 and 171833.0003). Screening PIK3R1 for mutations in 4 more affected individuals from 3 families, including a patient previously studied by Bonnel et al. (2000), revealed a recurrent substitution (R649W; 171833.0004) in all 4 patients. Thauvin-Robinet et al. (2013) then sequenced PIK3R1 in a heterogeneous clinical group of 14 additional unrelated individuals with severe insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation, who had not previously been diagnosed with SHORT syndrome and who were negative for mutation in known lipodystrophy-associated genes. Three of the 14 patients had mutations in PIK3R1, including 1 with the recurrent R649W substitution and another with a 1-bp duplication at R649 (171833.0005).

In a 3-generation Norwegian family with SHORT syndrome originally described by Aarskog et al. (1983), Chudasama et al. (2013) performed whole-exome sequencing and identified a heterozygous missense mutation in the PIK3R1 gene (R649W) that segregated with disease in the family and was not found in 340 Norwegian controls. Sanger sequencing of DNA from a German mother and son with SHORT syndrome, originally reported by Koenig et al. (2003), revealed that they were also heterozygous for the PIK3R1 R649W mutation. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events.

Dyment et al. (2013) performed whole-exome sequencing in a girl with SHORT syndrome and her unaffected parents and identified a frameshift mutation in the PIK3R1 gene (171833.0006) that segregated with disease. Analysis of PIK3R1 in 3 more SHORT probands revealed the R649W mutation in an affected mother and 2 sons from an English family, originally reported by Bankier et al. (1995) and restudied by Reardon and Temple (2008), and in another patient. A PIK3R1 nonsense mutation was identified in the third patient. In a 10-year-old boy diagnosed with SHORT syndrome, previously studied by Reardon and Temple (2008), no disease-causing variant was detected by whole-exome sequencing; coverage for PIK3R1 was excellent, and there was no evidence of any structural variant. Dyment et al. (2013) noted that although the boy showed several core features of SHORT syndrome, his facial features appeared to be distinct from those of mutation-positive individuals. The authors suggested that SHORT syndrome is a highly specific diagnosis that relies heavily on the facial gestalt.

Associations Pending Confirmation

For discussion of a possible association between SHORT syndrome and variation in the PRKCE gene, see 176975.0001.