SHORT syndrome (OMIM-269880) is an acronym consisting of following clinical features: S- short stature; H- hyperextensibility of joints/ hernia (inguinal); O-ocular depression; R-rieger anomaly; and T-teething delay. The most consistent finding, lipodystrophy of face and upper trunk, was first reported in 1975 [1]. The phenotype has been expanding since then. There have been a total of 26 case reports in English literature till date. Autosomal dominant inheritance has been proposed [2]. Locus of the gene has not yet been delineated. A recent study had shown that this may be a contiguous gene deletion syndrome requiring deletion of 1 or more other genes in addition to BMP4 [3].We report an adolescent with features of lipodystrophy, short stature, ocular depression, megalocornea, iris hypoplasia with previously two unreported features of deviated nasal septum (DNS) and bilateral cryptorchid testis.

A 14-year-old boy, product of consanguineous marriage was referred for work-up of short stature and associated dysmorphology. He was born as full term normal vaginal delivery at home, and was small at birth. At 3 years of age, he was evaluated for bilateral undescended testis. He underwent exploratory laprotomy with right orchidopexy and left incomplete orchidopexy with plan to follow up for second stage left complete orchidopexy later. At 11 years, left testis was found to atrectic and, left testicular implant was placed in scrotum. Surgeons noticed obvious short stature and dysmorphology and referred the case. Child was proportionately short with a height of 124 cm (<3rd centile as per WHO growth charts) and US/LS ratio of 0.9. Bone age and height age were 10-12 years (by Guerlich and Pyle method) and 7.5 years, respectively. Evaluation revealed thin built with progeroid facies with loss of subcutaneous fat mainly in face, trunk and shoulders, maxillary hypoplasia and dimpled chin (Fig.1). His development had been normal but punctuated by delay in acquisition of speech. Ophthalmic evaluation revealed pseudoenopthalmos, megalocornea, iris hypoplasia, sphincteric atrophy, venous tortousity with disc pallor (Fig 2). There was no glaucoma or cataract. There was marked deviation of nasal septum to left side with secondary hypertrophy of turbinates. Secondary delay in eruption of permanent teeth was present. Rest of the systemic examination was not contributory.

Fig. 1 Shows loss of subcutaneous fat in face, megalocornea and deviated nasal septum.

Fig. 2 (a) Fundus showing disc pallor and venous tortousity.	(b) Eyes showing sphincteric atrophy and iris hypoplasia.

Growth hormone stimulation tests, tests for thyroid function, hormones of pituitary axis and calcium homeostasis were in normal range. Sonographic examination of renal system revealed no pathology. Echocardiography, brain stem auditory evoked response and neuroimaging of brain were normal. The mother was a nondiabetic with normal insulin and HbA1C levels. The levels of glucose, insulin and HbA1C were normal in the proband but were not done in the father. Comparative array genomic hybridization was done on genomic DNA using Illumina Human CytoSNP. This test did not reveal any deletion or duplication of known pathogenic loci. There was no mutation in the PITX2 gene either.

This case has all described features of acronym SHORT except hyperextensibility/hernia, which is not a consistent feature of this syndrome [2]. Joint hyperextensibility was found in only 35% of cases. Few cases of inguinal hernia have been reported [4,5]. The frequency of reported features mentioned in acronym SHORT has been reported as-Short stature (70%), Hyperextensibility (35%), Ocular depression (100%), Rieger anomaly (77%), and Teething delay (94%), [2]. Frequencies of other common features but not part of acronym SHORT in decreasing order of their occurrence are-lack of subcutaneous fat/very thin (100%), abnormal ears (95%), hypoplastic alae nasi (94%), normal intellect (90%), delayed bone age (82%), triangular face (80%), megalocornea (64%), micrognathia (65%). Clinical phenotype frequency suggest, that lipodystrophy and ocular depression are two unique and cardinal features present in all patients. Our patient also expressed this consistent phenotype besides two new previously unreported features viz., deviated nasal septum and bilateral cryptorchid testis.

Lipodystrophy is manifested mostly by lack of subcutaneous fat in face, chest and upper extremities, relatively sparing the legs. Lipodystrophy is not progressive, but seems to become apparent with age. Taken together, the predominant feature in SHORT syndrome is the lipodystrophy rather than short stature. Unfortunately, this cardinal feature is not mentioned in the mnemonic SHORT.

Autosomal dominant inheritance has been suggested but genetic basis of SHORT syndrome is currently poorly understood. Both autosomal dominant inheritance described by Gorlin, et al. [1] and autosomal recessive described by Sensenbrenner, et al. [4] have been postulated. Our case could be autosomal recessive as was born to consanguineous parents or could be sporadic [2]. A familial translocation t(1;4) (q31.2;q25) was identified, presumably disrupting the PITX2 locus, in a child with SHORT syndrome and his mother with Axenfeld-Rieger syndrome and polycystic ovary syndrome but the family demonstrated occurrence of both Reiger syndrome and insulin resistance[6].Our case did not demonstrate the insulin resistance and array was not contributory in our case.

BMP4 loss of function mutations have been described in patients with SHORT syndrome, Axenfeld-Rieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. The authors postulated the critical role of this in ocular development. Studies in animal models have shown that Bmp4 and Pitx2 act in a common pathway in craniofacial/dental and left-right asymmetry development [3]. However, the definite locus of SHORT syndrome gene still remains illusive.

Contributors: AS was involved in clinical case management and was the main author. RA did the opthalmoscopic evaluation and PS did the genetic studies.SK critically reviewed the manuscript, made the diagnosis and will act as guarantor for the manuscript

Funding: None; Competing interests: None stated.

1. Sensenbrenner JA, Hussels IE, Levin LS. A low birthweight syndrome,? Rieger syndrome. Birth Defects Orig Art Ser. 1975; 11:423-6.

2. Koenig R, Brendel L, Fuchs S. SHORT syndrome. Clin. Dysmorphol. 2003;12:45-9.

3. Reis LM,　Tyler RC,　Schilter KF,　Abdul-Rahman O,　Innis JW,　Kozel BA, et al . BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Hum Genet. 2011;130:495-504.

4. Gorlin RJ. A selected miscellany. Birth Defects Orig Art Ser. 1975;11:46-8.

5. Aarskog D,　Ose L,　Pande H,　Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes. Am J Med Genet.1983;15:29-38.

6. Karadeniz NN,　Kocak-Midillioglu I,　Erdogan D,　Bökesoy I.Is SHORT syndrome another phenotypic variation of PITX2? Am J Med Genet. 2004;130A:406-9.