How to Cite this Article: Phadke SR, Ranganath P, Boggula VR, Gupta D, Phadke RV, Sloman M, Turnpenny PD. 2012. Brothers with hypospadias, vertebral segmentation defects, and intellectual disability: New syndrome? Am J Med Genet Part A 158A: 3065–3070.
The spondylocostal dysostoses (SCD: OMIM #122600; #277300; #608681; #609813; #613686) comprise a heterogeneous group of disorders characterized radiologically by multiple vertebral segmentation defects (MVSD) with fused and/or absent ribs. Monogenic forms of SCD, following autosomal recessive inheritance, due to mutations in the Notch pathway genes DLL3, MESP2, LFNG, and HES7, are characterized by extensive and contiguous MVSD with a general overall symmetry in the thoracic cage [Offiah et al., 2010]. Affected individuals have a variable degree of truncal shortness, a short neck, and mild, usually non-progressive, scoliosis. A further listed OMIM entity is the Casamassima–Morton–Nance syndrome [SCD with anal and urogenital anomalies (#271520), Casamassima et al., 1981], although the small number of reported cases are phenotypically diverse.
We report here on two brothers, born to nonconsanguineous parents, with short stature, hypospadias, scoliosis, vertebral segmentation defects, and intellectual disability. We compare the clinical findings in the brothers to those described in syndromes with some overlap, and conclude that they may represent a previously unreported syndrome, most likely following autosomal recessive inheritance, or possibly X-linked inheritance.
Two brothers from North India of age 16 and 14 years were referred for evaluation of hypospadias, short stature and poor school performance. They were the 3rd and 4th of five offspring of nonconsanguineous Muslim parents, their other children being normal. Apart from the external genitalia, no other obvious external malformations had been noted by the parents. However, the boys were perceived to have stunted linear growth since early childhood. Although both boys had normal developmental milestones through infancy and early childhood, they were found to have an inadequate educational performance from the time they started school. Neither had a history suggestive of systemic illness.
On examination, the older boy was found to have a height of 136 cm (<3rd centile; >5 SD below mean for age), weight 45 kg (3rd centile), arm span 158 cm (span: height ratio 1.16), upper segment/lower segment ratio 0.83, and head circumference 51 cm. His pubertal development corresponded to Tanner stage 5. He had a square-shaped jaw and slightly high-placed ears (Fig. 1). His incisor teeth were peg-shaped. He had grade 2 clubbing of all digits of hands and feet. In addition, there was cutaneous syndactyly and mild swan neck deformity of all fingers. The trunk appeared disproportionately short in comparison to the rest of his body and there was mild thoraco-lumbar scoliosis (Fig. 2). There were no other obvious skeletal or joint deformities. He had penoscrotal hypospadias that had been partially corrected surgically. The scrotal sacs were well developed, both testes were palpable and the testicular volume was 15 ml bilaterally. The cardiovascular and respiratory systems and abdomen were normal. His intelligence quotient (IQ) was formally tested (using the Standard and Coloured Progressive Matrices technique) and was found to be 50. The central nervous system status was normal.
The younger sib had a height of 135 cm (<3rd centile; >3.5 SD below mean for age), weight 44 kg (∼25th centile), arm span 156.5 cm (span: height ratio 1.16), upper segment/lower segment ratio 0.81, and head circumference 52 cm. His pubertal development corresponded to Tanner stage 3. He also had slightly high-placed ears like his brother, but no other obvious facial anomalies (Fig. 1). There was mild cutaneous syndactyly and mild swan neck deformity of the fingers, but no clubbing (Fig. 3). He had penile hypospadias. The scrotum was well formed, both testes were descended and the testicular volume was approximately 10 ml bilaterally. He also had thoraco-lumbar scoliosis (Fig. 2). The remainder of the skeletal system and other systems were normal. His IQ was formally assessed to be 65 using the Standard and Coloured Progressive Matrices technique. The boys' father appeared to be normal clinically. The mother and the other three siblings were not available for clinical evaluation but were normal according to the father's description.
Extensive investigations were performed on the older brother. Hematological and biochemical parameters including a random blood sugar, serum creatinine, lipid profile, serum calcium and phosphorus, serum electrolytes and liver function tests, and thyroid function, were all normal. A whole body skeletal survey revealed multiple segmentation and fusion defects involving the entire length of the thoracic and lumbar vertebral spine, including hemivertebrae and “butterfly shaped” vertebrae (Fig. 4). He had mild scoliosis centered on the thoraco-lumbar region. The ribs and the remainder of the skeletal system showed no significant abnormalities. The carpal bones and long bones were normal. A 550-band level karyotype was normal. The younger brother also had a normal karyotype and similar MVSD of the thoraco-lumbar spine.
A whole genome screen for known pathogenic microdeletions, and subtelomeric regions for copy number variations using the MLPA (Multiplex Ligation-dependent Probe Amplification) technique (the SALSA MLPA kit P245 microdeletion syndromes-1 kit for 21 microdeletion syndromes and the SALSA MLPA P070 and P036 subtelomeric loci mix; MRC-Holland, Amsterdam, Netherlands) in the older brother did not reveal any genomic imbalance. Microarray analysis using the Human CytoSNP—12 Bead Chip (Illumina, Inc., San Diego, CA) revealed the presence of a ∼2.4 Mb long region of duplication in the 9q22 region and an ∼8 Mb long copy neutral LOH (loss of heterozygosity) region in the 9q33 region in both sibs. In addition, the older brother had copy neutral LOH regions on 3p12, 8q12, and 12p12, and the younger sib had a 480 kb long duplication on 6q26 and copy neutral LOH regions on 2q32, 9q33, and 10q23. Neither sib had microdeletions. The father's microarray study did not show either of the copy number variations (CNVs) seen in his two affected offspring. Unfortunately, the mother's sample could not be procured for testing. Sequence analysis of Notch pathway genes was performed in the older brother as follows: exons 2–9 and flanking intronic regions of DLL3 (NM_016941.3); coding region and splice sites of MESP2 (NM_001039958.1); coding and flanking intronic regions of LFNG (NM_001040167.1), and HES7 (NM_032580.2). No variants from normal sequence were found.
The sibs reported here have disproportionate short stature with predominant truncal shortness, due to MVSD and fusion. They do not have the “crab-like” chest deformity or rib abnormalities typical of spondylothoracic dysostosis [OMIM #277300, Cornier et al., 2008; Offiah et al., 2010] but the pattern of vertebral anomalies, demonstrating generalized involvement throughout the spine, is similar to that seen in SCD. However, the Notch pathway genes analyzed (DLL3, MESP2, LFNG, and HES7), and found to be normal, are typically associated with non-syndromic SCD [Turnpenny et al., 2010], and these sibs had additionally hypospadias, partial cutaneous syndactyly, swan neck deformity of fingers, and intellectual disability. Anal atresia and meningomyelocoele have been described in association with many cases of SCD [Turnpenny et al., 2007], and urogenital abnormalities have been described with SCD in the poorly defined Casamassima–Morton–Nance syndrome [OMIM # 271520, Casamassima et al., 1981]. Intellectual disability has not been reported in any sub-types of SCD. The associated findings in these brothers bear a passing resemblance to Aarskog–Scott syndrome, Coffin Lowry syndrome, alpha-thalassemia X-linked mental retardation syndrome, the FG syndrome, and Börjeson–Forssman–Lehmann syndrome [Young, 1988; Teebi et al., 1993; Gibbons et al., 1995; Graham et al., 1999; Gecz et al., 2006]. However, an objective comparison of the manifestations in our cases with the typical phenotype of these conditions revealed significant points of difference (Table I), making these diagnoses unlikely.
Table I. Comparison of Manifestations of Our Cases With Those of Known Similar Syndromes
Alpha thalassemia X linked intellectual disability syndrome
The present cases
Short stature with truncal shortness with normal limb length
Short stature with moderate obesity
Short stature with truncal shortness with normal limb length
Normal joints, normal skin, no sternal deformity, normal appearing umbilicus, normal haematological parameters
X-linked; some reports suggestive of autosomal dominant inheritance
Possible autosomal recessive/X-linked/? autosomal recessive
The only common change identified in both the sibs in the microarray study was a duplicated region in the 9q22 region. As the probability of two siblings developing the same pathogenic CNV de novo is very low, and the father does not have this CNV, this common microduplicated region has almost certainly been inherited from their mother, who unfortunately was not available for testing. Of the 18 known genes present within this region (BARX1; PTPDC1; PTPDC1; MIRLET7A1; MIRLET7F1; MIRLET7D; ZNF169; FAM22F; HIATL1; FBP2; FBP1; C9orf3; MIR2278; MIR23B; MIR27B; MIR24-1; FANCC; PTCH1; C9orf130; NAG11; C9orf102; and NCRNA00092), seven of which encode for miRNAs, none have been reported to be associated with abnormal genital development, vertebral defects or intellectual disability.
The copy neutral LOH region common to both the sibs on 9q33 also encompasses some 60 known genes; however, none of these have been reported to have any significant contribution in genital, vertebral or mental development. As the two sibs are of nonconsanguineous parentage, the presence of a shared LOH region in the two affected siblings is of uncertain significance.
We propose that the two brothers described here have a new, previously unreported syndrome, most likely following autosomal recessive inheritance. Neither X-linked inheritance nor parental germline mosaicism for a disorder following autosomal dominant inheritance has been excluded. Further molecular genetic studies are required to determine the genetic basis of this condition.