RESEARCH LETTER
STAR Syndrome is Part of the Differential Diagnosis of Females with Anorectal Malformations Yuri A. Zarate,1* Jessica M. Farrell,2 Maria P. Alfaro,3 and Nahed O. Elhassan2 1
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
2
Division of Neonatology, University of Arkansas for Medical Sciences, Little Rock
3
Molecular Genetic Pathology, Arkansas Children’s Hospital, Little Rock, Arkansas
Manuscript Received: 23 January 2015; Manuscript Accepted: 23 January 2015
TO THE EDITOR: Anorectal malformations (ARM) are relatively common forms of congenital urorectal anomalies with an estimated incidence of one in 2,500 live births [Cuschieri and Group, 2001]. The incidence of associated anomalies varies between 40% and 70% [Wijers et al., 2014]. While the etiology of ARM is not completely known yet, it appears to be multifactorial with both genetic and environmental factors [Moore, 2013]. STAR syndrome (OMIM 300707) is an Xlinked dominant developmental disorder whose features include toe syndactyly, telecanthus, and anogenital/renal malformations [Unger et al., 2008]. In the handful of reported cases, point mutations and deletions of the FAM58A gene have been found [Unger et al., 2008; Boone et al., 2010]. We provide the clinical description of what is only the 8th well characterized female affected with this condition while reviewing all previously reported cases. We make particular emphasis on the distinctive features of this condition that allow a clinical diagnosis in the sometimes complicated evaluation of newborns with ARM or suspected VACTERL (Vertebral defects, Anal atresia, Cardiac anomalies, Tracheo– Esophageal fistula with esophageal atresia, Renal anomalies, and Limb anomalies) association. The Hispanic newborn female was born at 38 2/7 weeks gestation by spontaneous vaginal delivery. Family history was otherwise unremarkable and consanguinity was denied. There were no pregnancy complications or toxic exposures. Her birth weight was 2.923 kg (24rd centile), length 50 cm (68th centile), and her head circumference 33 cm (23rd centile). At the time of birth, she was noted to have dysmorphic features, an imperforate anus with stool coming through the vaginal opening, an enlarged clitoris, and 3–5 bilateral toe syndactyly (Fig. 1). Examination of her feet also revealed what appeared to be underdeveloped talus leading to radiographic evaluation that documented bilateral forefoot and hindfoot valgus deformities. An Ophthalmological exam was performed and yielded normal results while an echocardiogram revealed a moderate patent foramen ovale. A renal ultrasound showed a left multicystic, dysplastic kidney and a right mildly low lying kidney with duplicated collecting system, and a normal voiding cystourethrogram. A pelvic ultrasound showed normal uterus and bilateral ovaries while a head ultrasound showed a 5 mm right choroid cyst. The patient underwent diverting colostomy
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Zarate YA, Farrell JM, Alfaro MP, Elhassan NO. 2015. STAR syndrome is part of the differential diagnosis of females with anorectal malformations. Am J Med Genet Part A 167A:1940–1943.
placement on day of life 2 and noted intraoperatively to have a rectovaginal fistula. As part of her evaluation total cholesterol level was obtained and determined to be normal. Using the Affymetrix Cytoscan HD whole genome SNP array (Santa Clara, CA), she was found to have a heterozygous genomic loss of 232 kb at Xq28 (NCBI build hg19: chrX:152,859,010–153,090,834) that included 10 OMIM genes (FAM58A, DUSP9, PNCK, SLC6A8, BCAP31, ABCD1, PLXNB3, IDH3G, SSR4, and PDZD4) (Supplementary Figure in supporting information online). The X chromosome inactivation studies, as determined by DNA methylation of the CAG repeat at the androgen receptor locus, revealed a fully skewed pattern of inactivation of 100:0. A SNP array on the patient’s mother did not reveal the same deletion. The patient was successfully discharged home at 1 month of age. By 3 months of age she continued to have normal growth: weight was 5 kg (11th centile), length was 56.8 cm (8th centile), and head circumference was 38.6 cm (23rd centile). The differential diagnosis of patients with ARM that also have multiple congenital anomalies, includes the VACTERL association as well as a variety of single-gene-related syndromes and chromosomal anomalies [Solomon et al., 2012]. Not surprisingly, chromosomal microarray is the single test most frequently offered in the postnatal setting in patients being evaluated for possible VACTERL Conflict of interest: none. Correspondence to: Yuri A. Zarate, M.D., Arkansas Children’s Hospital, 1 Children’s Way; Slot 512-22, Little Rock, AR 72202. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 6 April 2015 DOI 10.1002/ajmg.a.37078
1940
ZARATE ET AL.
1941
FIG. 1. Patient at 3 weeks of age. Left: note the telecanthus, wide nasal bridge, and micrognathia. Right: Syndactyly of toes 3–5 was also seen.
association [Solomon et al., 2012]. It was through this test that we were able to find a pathogenic deletion in our patient, supporting the previous recommendation that analysis for copy number variants in this setting is warranted [Solomon et al., 2014]. In 2008, Unger et al. described four unrelated girls and a mother– daughter pair (this pair had been reported previously in Green et al.) with a constellation of toe syndactyly, telecanthus, anogenital/ renal malformations, and mutations for in FAM58A gene [Green et al., 1996; Unger et al., 2008]. The author suggested the acronym “STAR syndrome” and postulated an X-linked dominant pattern of inheritance with male lethality. A single extra case was briefly described in a subsequent paper and with similar clinical features, bringing the total to seven cases (Table I) [Boone et al., 2010]. The case here presented not only had the clinical findings previously described but also hindfoot and forefoot valgus deformities. Furthermore even though growth retardation has been determined to also be a key feature of the condition, our patient had normal anthropometric parameters during the first months of life.
The function of the FAM58A gene remained completely unknown until recently. Cyclin M, the product of FAM58A, is a binding partner of Cyclin-dependent kinase 10 (CDK10). In turn, this CDK10/cyclin M heterodimer appears to be involved in control of cell division and development [Unger et al., 2008]. It is speculated that females affected by the STAR syndrome have compromised CDK10/cyclin M kinase activity that result in the clinical findings depending on the tissues and timing of developmental stages [Guen et al., 2013]. Heterozygous deletions and intragenic mutations have been found with the same frequency so far. Except for the daughter of an affected mother, all mutations and deletions have been sporadic. In our case we were only able to confirm that deletion was not maternally inherited. Given the highly suspected X-linked dominant inheritance, and the lack of features in her father, we can say that her deletion was also most likely de novo in origin. The present case constitutes the largest deletion encompassing FAM58A in a patient with STAR syndrome reported so far. There were three other genes
Coronal and lambdoid craniosynostosis; epilepsy; syringomyelia
Lower lid coloboma
þ
þ þ
þ
þ þ þ þ þ
De novo Complete
Deletion exons 1 þ 2
Female 40 kb (152,860,970–152,901,037)*
Unger et al. (Case 1)
PFO; PPAS Macular hypoplasia
þ þ
þ
555 þ 1G>A Splice site intron 4 De novo Almost complete þ þ þ þ þ
Female
Unger et al. (case 2)
Sagittal craniosynostosis
BAV; PVS Dystrophic retina; myopia Radial ray
þ
þ þ
þ
þ þ þ þ þ
De novo Complete
Deletion of exon 5
Female 4 kb (152,850,929–152,855,177)*
Unger et al. (case 3)
ASD Normal
þ
þ
þ
þ þ þ þ þ
201dupT Frameshift mutation De novo Complete
Female
Unger et al. (case 4)
þ
þ
þ
þ
– – þ þ þ
556 1G>A Splice site intron 4 De novo Complete
Female
Unger et al. (case 5)
þ þ
þ
þ
– (low set) þ þ þ
Maternal Complete
556 1G>A Splice site intron 4
Female
Unger et al. (case 6)
Vertebral/rib, middle phalanges
ASD, VSD
þ
þ
þ (low set) þ þ þ
De novo Complete
Deletion of exon 5
Female 8–10 kb (152,841,547– 152,857,654)*
Boone et al.
þ þ þ PFO Normal Hindfoot and forefoot valgus deformities Choroid plexus cyst
þ
þ – þ þ
Not maternal Complete
Deletion of all exons
Female 232 kb (152,859,010– 153,090,834)
This report
Coordinates converted from NCBI build hg18. þ and indicate that a trait is present or absent, respectively. ASD, atrial septal defect; BAV, bicuspid aortic valve; ESRD, end stage renal disease; MCDK, multicystic dysplastic kidney; PFO, patent foramen ovale; PPAS, peripheral pulmonary artery stenosis; PVS, pulmonary valve stenosis; VSD, ventricular septal defect; VU, vesicoureteral.
*
Other
Telecanthus Lop ears Clinodactyly 5th finger Syndactyly of toes (not 2–3) Anal atresia Genital anomaly Small labia majora Large clitoris Duplicated vagina Duplicated uterus (partial) Renal/urinary tract anomaly VU reflux Hydronephrosis Single/fused kidney ESRD MCDK Pelvic/low kidney Duplicated collecting system Congenital heart disease Eyes Skeletal Anomalies
Inheritance Skewing X-chromosome
Gender Xq28 deletion Size (NCBI build hg19 coordinates) FAM58A mutation Predicted alteration of FAM58A
Feature
TABLE I. Clinical Features in STAR Syndrome Cases
1942 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
ZARATE ET AL. with associated phenotypes that were also deleted in this patient and that made counseling more challenging. The ABCD1 gene deletion would make this patient a carrier for X-linked adrenoleukodystrophy (OMIM 300100). Female carriers of this condition have been found to have a high frequency of myelopathy and/or peripheral neuropathy that seems to correlate with age but independent of the X-inactivation pattern [Engelen et al., 2014]. Similarly, female heterozygous for mutations in the SLC6A8 can have symptoms of cerebral creatine deficiency syndrome (OMIM 300352) such as intellectual disability that do not correlate with X-inactivation skewing in blood [van et al., 2011]. Lastly, carriers of mutations and contiguous deletions affecting the BCAP31 gene that results in deafness, dystonia, and cerebral hypomyelination (OMIM 300475), do not seem to be affected although only a few cases have been reported [Cacciagli et al., 2013; Calhoun and Raymond, 2014]. Despite the great physical and social burden on ARM patients and their parents, for the majority of patients, the etiology is largely unknown and attributed to be multifactorial. While most cases of ARM are not part of a recognizable syndrome, between 2 and 8% of patients with ARM have an affected first or second-degree relative [Wijers et al., 2014]. Most reported cases of STAR syndrome so far have been de-novo and provide the basis for a low recurrence risk. However, the previous report of a mother–daughter duo, the theoretical possibility of gonadal mosaicism, and the potential phenotype variability depending on “favorable” skewing of X chromosome inactivation, are enough reasons to justify parental testing. For females affected with STAR syndrome, germline mutations will result in 50% of the female offspring having this condition, and 50% of the male offspring probably being non-viable. In summary, STAR syndrome remains a very rare described entity with only eight well described cases that we have here reviewed. The combination of toe syndactyly (other than 2-3), telecanthus, and anogenital/renal malformations seems unique enough to suggest a clinical diagnosis in the sometimes complicated diagnostic evaluation of patients with ARM or VACTERL association. High resolution microarray could be useful in detecting deletions affecting FAM58A as illustrated in this case while X chromosome inactivation studies always show high skewing.
REFERENCES
1943 Girard N, Sarda P, Boespflug-Tanguy O, Villard L. 2013. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet 93:579–586. Calhoun AR, Raymond GV. 2014. Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. Am J Med Genet A 164A:2613–2617. Cuschieri A, Group EW. 2001. Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million births in Europe. Am J Med Genet 103:207–215. Engelen M, Barbier M, Dijkstra IM, Schur R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, PollThe BT, Kemp S. 2014. X-linked adrenoleukodystrophy in women: A cross-sectional cohort study. Brain 137:693–706. Green AJ, Sandford RN, Davison BC. 1996. An autosomal dominant syndrome of renal and anogenital malformations with syndactyly. J Med Genet 33:594–596. Guen VJ, Gamble C, Flajolet M, Unger S, Thollet A, Ferandin Y, SupertiFurga A, Cohen PA, Meijer L, Colas P. 2013. CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. Proc Natl Acad Sci USA 110:19525–19530. Moore SW. 2013. Associations of anorectal malformations and related syndromes. Pediatr Surg Int 29:665–676. Solomon BD, Baker LA, Bear KA, Cunningham BK, Giampietro PF, Hadigan C, Hadley DW, Harrison S, Levitt MA, Niforatos N, Paul SM, Raggio C, Reutter H, Warren-Mora N. 2014. An approach to the identification of anomalies and etiologies in neonates with identified or suspected VACTERL (vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, cardiac anomalies, renal anomalies, and limb anomalies) association. J Pediatr 164:e451–e457. Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, Tibboel D, Reutter H, Giampietro PF. 2012. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A 158A:3087–3100. Unger S, Bohm D, Kaiser FJ, Kaulfuss S, Borozdin W, Buiting K, Burfeind P, Bohm J, Barrionuevo F, Craig A, Borowski K, Keppler-Noreuil K, Schmitt-Mechelke T, Steiner B, Bartholdi D, Lemke J, Mortier G, Sandford R, Zabel B, Superti-Furga A, Kohlhase J. 2008. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nat Genet 40:287–289. van de Kamp JM, Mancini GM, Pouwels PJ, Betsalel OT, van Dooren SJ, de Koning I, Steenweg ME, Jakobs C, van der Knaap MS, Salomons GS. 2011. Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264–272.
Boone PM, Bacino CA, Shaw CA, Eng PA, Hixson PM, Pursley AN, Kang SH, Yang Y, Wiszniewska J, Nowakowska BA, del Gaudio D, Xia Z, Simpson-Patel G, Immken LL, Gibson JB, Tsai AC, Bowers JA, Reimschisel TE, Schaaf CP, Potocki L, Scaglia F, Gambin T, Sykulski M, Bartnik M, Derwinska K, Wisniowiecka-Kowalnik B, Lalani SR, Probst FJ, Bi W, Beaudet AL, Patel A, Lupski JR, Cheung SW, Stankiewicz P. 2010. Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 31:1326–1342.
SUPPORTING INFORMATION
Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Levy N,
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Wijers CH, van Rooij IA, Marcelis CL, Brunner HG, de Blaauw I, Roeleveld N. 2014. Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review. Birth Defects Res C Embryo Today 102:382–400.
STAR Syndrome is Part of the Differential Diagnosis of Females with Anorectal Malformations Yuri A. Zarate,1* Jessica M. Farrell,2 Maria P. Alfaro,3 and Nahed O. Elhassan2 1
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
2
Division of Neonatology, University of Arkansas for Medical Sciences, Little Rock
3
Molecular Genetic Pathology, Arkansas Children’s Hospital, Little Rock, Arkansas
Manuscript Received: 23 January 2015; Manuscript Accepted: 23 January 2015
TO THE EDITOR: Anorectal malformations (ARM) are relatively common forms of congenital urorectal anomalies with an estimated incidence of one in 2,500 live births [Cuschieri and Group, 2001]. The incidence of associated anomalies varies between 40% and 70% [Wijers et al., 2014]. While the etiology of ARM is not completely known yet, it appears to be multifactorial with both genetic and environmental factors [Moore, 2013]. STAR syndrome (OMIM 300707) is an Xlinked dominant developmental disorder whose features include toe syndactyly, telecanthus, and anogenital/renal malformations [Unger et al., 2008]. In the handful of reported cases, point mutations and deletions of the FAM58A gene have been found [Unger et al., 2008; Boone et al., 2010]. We provide the clinical description of what is only the 8th well characterized female affected with this condition while reviewing all previously reported cases. We make particular emphasis on the distinctive features of this condition that allow a clinical diagnosis in the sometimes complicated evaluation of newborns with ARM or suspected VACTERL (Vertebral defects, Anal atresia, Cardiac anomalies, Tracheo– Esophageal fistula with esophageal atresia, Renal anomalies, and Limb anomalies) association. The Hispanic newborn female was born at 38 2/7 weeks gestation by spontaneous vaginal delivery. Family history was otherwise unremarkable and consanguinity was denied. There were no pregnancy complications or toxic exposures. Her birth weight was 2.923 kg (24rd centile), length 50 cm (68th centile), and her head circumference 33 cm (23rd centile). At the time of birth, she was noted to have dysmorphic features, an imperforate anus with stool coming through the vaginal opening, an enlarged clitoris, and 3–5 bilateral toe syndactyly (Fig. 1). Examination of her feet also revealed what appeared to be underdeveloped talus leading to radiographic evaluation that documented bilateral forefoot and hindfoot valgus deformities. An Ophthalmological exam was performed and yielded normal results while an echocardiogram revealed a moderate patent foramen ovale. A renal ultrasound showed a left multicystic, dysplastic kidney and a right mildly low lying kidney with duplicated collecting system, and a normal voiding cystourethrogram. A pelvic ultrasound showed normal uterus and bilateral ovaries while a head ultrasound showed a 5 mm right choroid cyst. The patient underwent diverting colostomy
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Zarate YA, Farrell JM, Alfaro MP, Elhassan NO. 2015. STAR syndrome is part of the differential diagnosis of females with anorectal malformations. Am J Med Genet Part A 167A:1940–1943.
placement on day of life 2 and noted intraoperatively to have a rectovaginal fistula. As part of her evaluation total cholesterol level was obtained and determined to be normal. Using the Affymetrix Cytoscan HD whole genome SNP array (Santa Clara, CA), she was found to have a heterozygous genomic loss of 232 kb at Xq28 (NCBI build hg19: chrX:152,859,010–153,090,834) that included 10 OMIM genes (FAM58A, DUSP9, PNCK, SLC6A8, BCAP31, ABCD1, PLXNB3, IDH3G, SSR4, and PDZD4) (Supplementary Figure in supporting information online). The X chromosome inactivation studies, as determined by DNA methylation of the CAG repeat at the androgen receptor locus, revealed a fully skewed pattern of inactivation of 100:0. A SNP array on the patient’s mother did not reveal the same deletion. The patient was successfully discharged home at 1 month of age. By 3 months of age she continued to have normal growth: weight was 5 kg (11th centile), length was 56.8 cm (8th centile), and head circumference was 38.6 cm (23rd centile). The differential diagnosis of patients with ARM that also have multiple congenital anomalies, includes the VACTERL association as well as a variety of single-gene-related syndromes and chromosomal anomalies [Solomon et al., 2012]. Not surprisingly, chromosomal microarray is the single test most frequently offered in the postnatal setting in patients being evaluated for possible VACTERL Conflict of interest: none. Correspondence to: Yuri A. Zarate, M.D., Arkansas Children’s Hospital, 1 Children’s Way; Slot 512-22, Little Rock, AR 72202. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 6 April 2015 DOI 10.1002/ajmg.a.37078
1940
ZARATE ET AL.
1941
FIG. 1. Patient at 3 weeks of age. Left: note the telecanthus, wide nasal bridge, and micrognathia. Right: Syndactyly of toes 3–5 was also seen.
association [Solomon et al., 2012]. It was through this test that we were able to find a pathogenic deletion in our patient, supporting the previous recommendation that analysis for copy number variants in this setting is warranted [Solomon et al., 2014]. In 2008, Unger et al. described four unrelated girls and a mother– daughter pair (this pair had been reported previously in Green et al.) with a constellation of toe syndactyly, telecanthus, anogenital/ renal malformations, and mutations for in FAM58A gene [Green et al., 1996; Unger et al., 2008]. The author suggested the acronym “STAR syndrome” and postulated an X-linked dominant pattern of inheritance with male lethality. A single extra case was briefly described in a subsequent paper and with similar clinical features, bringing the total to seven cases (Table I) [Boone et al., 2010]. The case here presented not only had the clinical findings previously described but also hindfoot and forefoot valgus deformities. Furthermore even though growth retardation has been determined to also be a key feature of the condition, our patient had normal anthropometric parameters during the first months of life.
The function of the FAM58A gene remained completely unknown until recently. Cyclin M, the product of FAM58A, is a binding partner of Cyclin-dependent kinase 10 (CDK10). In turn, this CDK10/cyclin M heterodimer appears to be involved in control of cell division and development [Unger et al., 2008]. It is speculated that females affected by the STAR syndrome have compromised CDK10/cyclin M kinase activity that result in the clinical findings depending on the tissues and timing of developmental stages [Guen et al., 2013]. Heterozygous deletions and intragenic mutations have been found with the same frequency so far. Except for the daughter of an affected mother, all mutations and deletions have been sporadic. In our case we were only able to confirm that deletion was not maternally inherited. Given the highly suspected X-linked dominant inheritance, and the lack of features in her father, we can say that her deletion was also most likely de novo in origin. The present case constitutes the largest deletion encompassing FAM58A in a patient with STAR syndrome reported so far. There were three other genes
Coronal and lambdoid craniosynostosis; epilepsy; syringomyelia
Lower lid coloboma
þ
þ þ
þ
þ þ þ þ þ
De novo Complete
Deletion exons 1 þ 2
Female 40 kb (152,860,970–152,901,037)*
Unger et al. (Case 1)
PFO; PPAS Macular hypoplasia
þ þ
þ
555 þ 1G>A Splice site intron 4 De novo Almost complete þ þ þ þ þ
Female
Unger et al. (case 2)
Sagittal craniosynostosis
BAV; PVS Dystrophic retina; myopia Radial ray
þ
þ þ
þ
þ þ þ þ þ
De novo Complete
Deletion of exon 5
Female 4 kb (152,850,929–152,855,177)*
Unger et al. (case 3)
ASD Normal
þ
þ
þ
þ þ þ þ þ
201dupT Frameshift mutation De novo Complete
Female
Unger et al. (case 4)
þ
þ
þ
þ
– – þ þ þ
556 1G>A Splice site intron 4 De novo Complete
Female
Unger et al. (case 5)
þ þ
þ
þ
– (low set) þ þ þ
Maternal Complete
556 1G>A Splice site intron 4
Female
Unger et al. (case 6)
Vertebral/rib, middle phalanges
ASD, VSD
þ
þ
þ (low set) þ þ þ
De novo Complete
Deletion of exon 5
Female 8–10 kb (152,841,547– 152,857,654)*
Boone et al.
þ þ þ PFO Normal Hindfoot and forefoot valgus deformities Choroid plexus cyst
þ
þ – þ þ
Not maternal Complete
Deletion of all exons
Female 232 kb (152,859,010– 153,090,834)
This report
Coordinates converted from NCBI build hg18. þ and indicate that a trait is present or absent, respectively. ASD, atrial septal defect; BAV, bicuspid aortic valve; ESRD, end stage renal disease; MCDK, multicystic dysplastic kidney; PFO, patent foramen ovale; PPAS, peripheral pulmonary artery stenosis; PVS, pulmonary valve stenosis; VSD, ventricular septal defect; VU, vesicoureteral.
*
Other
Telecanthus Lop ears Clinodactyly 5th finger Syndactyly of toes (not 2–3) Anal atresia Genital anomaly Small labia majora Large clitoris Duplicated vagina Duplicated uterus (partial) Renal/urinary tract anomaly VU reflux Hydronephrosis Single/fused kidney ESRD MCDK Pelvic/low kidney Duplicated collecting system Congenital heart disease Eyes Skeletal Anomalies
Inheritance Skewing X-chromosome
Gender Xq28 deletion Size (NCBI build hg19 coordinates) FAM58A mutation Predicted alteration of FAM58A
Feature
TABLE I. Clinical Features in STAR Syndrome Cases
1942 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
ZARATE ET AL. with associated phenotypes that were also deleted in this patient and that made counseling more challenging. The ABCD1 gene deletion would make this patient a carrier for X-linked adrenoleukodystrophy (OMIM 300100). Female carriers of this condition have been found to have a high frequency of myelopathy and/or peripheral neuropathy that seems to correlate with age but independent of the X-inactivation pattern [Engelen et al., 2014]. Similarly, female heterozygous for mutations in the SLC6A8 can have symptoms of cerebral creatine deficiency syndrome (OMIM 300352) such as intellectual disability that do not correlate with X-inactivation skewing in blood [van et al., 2011]. Lastly, carriers of mutations and contiguous deletions affecting the BCAP31 gene that results in deafness, dystonia, and cerebral hypomyelination (OMIM 300475), do not seem to be affected although only a few cases have been reported [Cacciagli et al., 2013; Calhoun and Raymond, 2014]. Despite the great physical and social burden on ARM patients and their parents, for the majority of patients, the etiology is largely unknown and attributed to be multifactorial. While most cases of ARM are not part of a recognizable syndrome, between 2 and 8% of patients with ARM have an affected first or second-degree relative [Wijers et al., 2014]. Most reported cases of STAR syndrome so far have been de-novo and provide the basis for a low recurrence risk. However, the previous report of a mother–daughter duo, the theoretical possibility of gonadal mosaicism, and the potential phenotype variability depending on “favorable” skewing of X chromosome inactivation, are enough reasons to justify parental testing. For females affected with STAR syndrome, germline mutations will result in 50% of the female offspring having this condition, and 50% of the male offspring probably being non-viable. In summary, STAR syndrome remains a very rare described entity with only eight well described cases that we have here reviewed. The combination of toe syndactyly (other than 2-3), telecanthus, and anogenital/renal malformations seems unique enough to suggest a clinical diagnosis in the sometimes complicated diagnostic evaluation of patients with ARM or VACTERL association. High resolution microarray could be useful in detecting deletions affecting FAM58A as illustrated in this case while X chromosome inactivation studies always show high skewing.
REFERENCES
1943 Girard N, Sarda P, Boespflug-Tanguy O, Villard L. 2013. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet 93:579–586. Calhoun AR, Raymond GV. 2014. Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. Am J Med Genet A 164A:2613–2617. Cuschieri A, Group EW. 2001. Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million births in Europe. Am J Med Genet 103:207–215. Engelen M, Barbier M, Dijkstra IM, Schur R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, PollThe BT, Kemp S. 2014. X-linked adrenoleukodystrophy in women: A cross-sectional cohort study. Brain 137:693–706. Green AJ, Sandford RN, Davison BC. 1996. An autosomal dominant syndrome of renal and anogenital malformations with syndactyly. J Med Genet 33:594–596. Guen VJ, Gamble C, Flajolet M, Unger S, Thollet A, Ferandin Y, SupertiFurga A, Cohen PA, Meijer L, Colas P. 2013. CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. Proc Natl Acad Sci USA 110:19525–19530. Moore SW. 2013. Associations of anorectal malformations and related syndromes. Pediatr Surg Int 29:665–676. Solomon BD, Baker LA, Bear KA, Cunningham BK, Giampietro PF, Hadigan C, Hadley DW, Harrison S, Levitt MA, Niforatos N, Paul SM, Raggio C, Reutter H, Warren-Mora N. 2014. An approach to the identification of anomalies and etiologies in neonates with identified or suspected VACTERL (vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, cardiac anomalies, renal anomalies, and limb anomalies) association. J Pediatr 164:e451–e457. Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, Tibboel D, Reutter H, Giampietro PF. 2012. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A 158A:3087–3100. Unger S, Bohm D, Kaiser FJ, Kaulfuss S, Borozdin W, Buiting K, Burfeind P, Bohm J, Barrionuevo F, Craig A, Borowski K, Keppler-Noreuil K, Schmitt-Mechelke T, Steiner B, Bartholdi D, Lemke J, Mortier G, Sandford R, Zabel B, Superti-Furga A, Kohlhase J. 2008. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nat Genet 40:287–289. van de Kamp JM, Mancini GM, Pouwels PJ, Betsalel OT, van Dooren SJ, de Koning I, Steenweg ME, Jakobs C, van der Knaap MS, Salomons GS. 2011. Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264–272.
Boone PM, Bacino CA, Shaw CA, Eng PA, Hixson PM, Pursley AN, Kang SH, Yang Y, Wiszniewska J, Nowakowska BA, del Gaudio D, Xia Z, Simpson-Patel G, Immken LL, Gibson JB, Tsai AC, Bowers JA, Reimschisel TE, Schaaf CP, Potocki L, Scaglia F, Gambin T, Sykulski M, Bartnik M, Derwinska K, Wisniowiecka-Kowalnik B, Lalani SR, Probst FJ, Bi W, Beaudet AL, Patel A, Lupski JR, Cheung SW, Stankiewicz P. 2010. Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 31:1326–1342.
SUPPORTING INFORMATION
Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Levy N,
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Wijers CH, van Rooij IA, Marcelis CL, Brunner HG, de Blaauw I, Roeleveld N. 2014. Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review. Birth Defects Res C Embryo Today 102:382–400.
