Coffin-Siris Syndrome in Two Sisters in Nepal

1Dr. Anil Ojha, MBBS, MD, Assistant Professor, Department of Paediatrics, Kathmandu Medical College and Teaching Hospital, Sinamangal, Kathmandu, Nepal, 2Dr. Chin-To Fong, Associate Professor and Chief, Division of Paediatric Genetics, Department of Paediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA, 3Dr. Arti Sharma Pandey Ph.D., Associate Professor and Head, Department of Biochemistry, Kathmandu Medical College, Basic Sciences Block, Duwakot, Bhaktapur, Nepal. Abstract


Introduction
C offi n-Siris syndrome (CSS) has been described as mental retardation associated with coarse facial features, hypertrichosis and hypoplastic or absent fi ngernails or toenails (OMIM 135900).Coffi n and Siris were the fi rst to describe three unrelated female children with severe mental and developmental retardation, sparse scalp hair, and coarse appearing facies with bushy eyebrows, a wide mouth, and thick lips 1 .A characteristic feature was brachydactyly of the fi fth digits of both hands and feet with absence of nails of terminal phalanges.
CSS is generally assumed to be inherited in an autosomal recessive manner, although autosomal dominant inheritance has not been formally excluded 2,3 .In 2001, Fleck et.al. proposed the minimal criteria for diagnosis of CSS which include some degree of developmental delay, coarse facial appearance, hirsutism, hypoplastic or absent fi fth fi ngernails or toenails, and hypoplastic or absent fi fth distal phalanges 4 .Recently, Schrier et al defi ned a "classic" and "variant" type of CSS to develop an algorithm to determine the likelihood of diagnosis of CSS 5 .
The only documented case of Coffi n Siris syndrome in South Asia is that of a nine year old girl in India who also had the Mayer-Rokitansky-Kuster-Hauser syndrome 6 .No other cases have been reported from the rest of the South Asian countries and the incidence of CSS in this region is unknown.We report here the case of CSS in two sisters in Nepal diagnosed with CSS on the basis of the algorithm developed by Schrier et al 5 .

The Case
Two sisters were identifi ed as having CSS at an Institute for mentally retarded children during a consultation visit to the center.After informing the parents, the family was called to Kathmandu Medical College, Department of Paediatrics, for a clinical examination.A thorough family history was taken.Both sisters were examined by an otorhinologist and advised for otoacoustic emission (OAE) test.Ophthalmic evaluation was also done.
The sisters were 11 and 8.5 years of age, born of non-consanguineous parents in the remote district of far western Nepal.Both girls were delivered at home and were reportedly small at birth.Dentition was delayed (1.5 years) and later, both showed marked cognitive and developmental delay and failure to thrive.Both girls showed intolerance for mother's milk since birth.The problem resolved by the time the girls were one year of age, but both continue to have frequent diarrheal episodes as well as infections.There was no history of seizures or heart disease.There is reportedly no history of a similar condition in either parent's side of family.
There was a family history of a growth on the back in girls' father, his younger brother and a younger sister, which suppurated and resulted in temporary paraplegia in all affected, and death of the sister at 9 years of age.The mother's fi rst born was unable to suckle and died at 15 days of age.The sisters have a younger brother who is unaffected.
General examination of the girls showed their height, weight and head circumference to be below the third percentile for age.They were proportionately short in stature.Both had marked cognitive and developmental delay.HEENT examination showed both sisters to have a high palate, a low hairline, sparse scalp hair and long eyelashes.Both had hypoplastic fi fth phalanx which was confi rmed by X-rays (Figure 1).Both also had dysplastic nails of fi fth digits in the upper limbs.The younger sibling had coarse facies, a depressed nasal bridge, bushy eyebrows and thick vermilion, and was hyperactive.The older sister had a thick vermilion, anteverted nares, thin eyebrows and upslanting of eyes.The examination of precordium and abdomen was not contributory.OAE and ophthalmic evaluations were normal.The algorithm developed by Schrier et al was followed to confi rm the diagnosis and determine the class of CSS, as shown in Table 1.

Discussion
Both sisters fi t the criteria for classic CSS, type A. Several translocations have been reported in individuals with CSS, and in particular, translocations involving 7q32-7q34 have been postulated as a candidate region 8,9 .Recently, the genes coding for the various subunits of the SWI/SNF complex, SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B, were found to be mutated in individuals clinically suspected of having CSS. 10 These studies also confi rmed the inheritance to be autosomal dominant.Since in the presented case, one daughter is deceased, and two are affected, with the only male child unaffected, it is likely that the father is the carrier of the mutation.A molecular investigation of the mutations of the SWI/SNF complex in the two sisters will follow, to relate the sisters' phenotype to a genotype.

Conclusion
Coffi n Syris syndrome is a rare form of congenital disorder inherited in autosomal recessive fashion presenting with mental retardation, coarse facial features, hypertrichosis and hypoplastic or absent fi ngernails or toenails.A clinical diagnosis of this condition requires at least one feature from three categories namely ectodermal, constitutional and organ related.It is important in our setting as we lack facilities for genetic studies.

Fig 1 :
Fig 1: Younger (left) and older (right) sisters with coarse facial features

Fig 3 :
Fig 3: Older sister showing hypoplastic fi nger nail and hypoplastic distal phalynx DD, CD with fi fth digit (Yes) DD: Developmental delay CD: Cognitive delay At least one feature from each category Ectodermal -long eyelashes, hypoplastic fi fth digit fi ngernails, late dentition Constitutional-microcephaly present, IUGR, short stature, FTT, frequent infections Organ related-(feeding/GI) indigestion, diarrhea, steatorrhea Exclusion of other syndromes (Yes) Mosaic trisomy 9-hirsutism absent, absence of bulbous nose Brachymorphism-Onychodysplasia-dysphalangism (BOD) -wide mouth and broad nose absent Deafness-Onychodystrophy-Osterodystrophy-Mental retardation (DOOR) -triphalangeal thumbs absent, deafness absent Fetal alcohol spectrum (mother does not drink alcohol) Fetal hydantoin/phenytoin embryopathy-Absence of small nails on all fi ngers, absence of large anterior fontanelle,, mother was not on any kind of drugs during pregnancy Mabryhyperphosphatasia mental retardation -seizures and hypotonia absent Cornelia de Lange Syndrome (CdLS) -synophrys and limb anomalies absent Combination of facial features Thick eyelashes and eyebrows, thick vermilion Both sisters have classic CSS, type A

Table 1 :
5riteria for diagnosis of CSS according to the algorithm by Schrier et al.5