Journal of Genetics, Vol. 97, No. 1, March 2018, pp. 205–211 © Indian Academy of Sciences https://doi.org/10.1007/s12041-018-0905-0

RESEARCH ARTICLE

Phenotypic characterization of derivative 22 syndrome: case series and review

DEEPTI SAXENA, PRIYANKA SRIVASTAVA, MONI TUTEJA, KAUSIK MANDAL and SHUBHA R PHADKE∗

Department of , Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India *For correspondence. E-mail: [email protected].

Received 4 May 2017; revised 20 July 2017; accepted 24 July 2017; published online 5 March 2018

Abstract. Emanuel syndrome is caused due to an additional derivative 22 and is characterized by severe , , , preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and genital abnormalities in males. In 99% of the cases, one of the parents is a carrier of balanced translocation between 11 and 22. It occurs due to malsegregation of the gametes with 3:1 segregation. In this case series, we describe four patients with diverse manifestations of this condition. The craniosynostosis observed in one case is a novel finding which has never been reported previously. This study aims to widen the phenotypic spectrum of Emanuel syndrome and provide cytogenetic microarray based breakpoints in two of the cases, thus supporting close clustering of the breakpoints of this common recurrent chromosomal rearrangement.

Keywords. Emanuel syndrome; derivative ; microarray; intellectual disability; chromosomal rearrangement.

Introduction microarray (CMA) was performed by the Cytogenetics 2.7M Array, Affymetrix. GRch 37: Feb 2009 (hg 19) Emanuel syndrome (OMIM: 609029), also known as human genome version was used to annotate the data. supernumerary derivative 22 syndrome, is characterized The important clinical features are given below. by developmental delay, facial dysmorphism, heart defect, genital abnormalities and renal anomalies. The patients have supernumerary marker chromosome (sSMC) com- Clinical features posed of chromosomal material from both chromosomes 11 and 22. It can be de novo or arise due to 3:1 meiotic seg- Case I is a 22 month old male child, referred in view of regation during gametogenesis in one of the parents having failure in gaining milestones and history of feeding dif- t(11;22)(q23;q11). Carriers of balanced translocation are ficulty. His motor milestones were grossly delayed and identified following recurrent abortions, infertility or after only babbling was present. He is the first child of non- birth of a child with der(22) syndrome. The translocation consanguineous parents, born at term with no history of carriers have 10% chance of having a child with Emanuel perinatal asphyxia. On examination, his weight was 9.4 kg syndrome (Fraccaro et al. 1980; Zackai et al., 1980). The (between –2 and –3 SD), length was 83 cm (between 10th exact incidence is not known. There are only 100 reported and 20th centile) and head circumference was 47 cm (30th cases. The actual number of cases found was markedly centile). Dysmorphic features including frontal bossing, less than the expected based on theoretical calculations in curly and sparse hair, sparse and interrupted eyebrows, Japan (Ohye et al. 2014). downward slanting eyes, left preauricular pit, fullness of cheeks, short stubby nose, upturned nares, thickened alae Methods and results nasi, long philtrum and downturned mouth corners were Cases present (figure 1, a&b). Genitalia and rest of the systemic examination was within normal limits. The clinical details, including anthropometric measure- Routine haematological and biochemical investigations ments of all four cases are given in table 1. Chromosonal were normal. Eye examination, echocardiography,

205 206 Deepti Saxena et al. − Hypoplastic corpus callosum − + + spots café-au-lait external ear canal and small ossified middle ear ossicles multiple −− ++ Not done Not done + ++ CT scan – absence of right Right microtia,facial asymmetry, −− Mb at 22q fusion facial asymmetry and proptosis − −− − − Gain of 18 Mb at 11q and 3.6 Unilateral craniosynostosis, −− − at 22q + −−− −− −−−− −−− − 2015) ) et al. et al. Characteristic features of our patients with Emanuel syndrome. 2009) 2009) 2009) et al. et al. et al. Pallotta our case Frontal bossing + + Sparse hairSparse eyebrowsDownward slant eyesPreauricular pit (76%, + + + + + + + + + Long philtrum + Downturned mouth cornersMicrognathia (60%) + + + Parent of originKaryotype of carrier parent 46,XX,t(11;22)(q23:q11) Mother 46,XX,t(11;22)(q25;q13.1) 46,XX,t(11;22)(q25;q13) 46,XX,inv(9),t(11;22) Mother Mother Mother Cleft palate (50%, Carter Heart defects (57%, Carter Renal defects (36%, Carter CNS anomalies (30%, New or unique features in Neuroimaging (CT/ MRI) Normal CT scan – right coronal suture of probandFISHCytogenetic microarray 47,+mar Gain of 18 Mb at 11q and 3.4 Mb 22q11.2 47,+mar 22q11.2 trisomy 47,+mar Not done 47,XX,+der(22),t(11;22) Not done Kapoor Table 1. Clinical featureFacial dysmorphism Case I Case II Case III Case IV Other features Cytogenetics Case series of Emanuel syndrome 207

Figure 1. (a) Case I showing dysmorphic features including frontal bossing, interrupted eyebrows, downward slanting eyes, fullness of cheeks, short stubby nose, upturned nares, thickened alae nasi, long philtrum and downturned mouth corners, (b) Left preauricular pit. (c–d) Case II showing bilateral proptosis, gross cranial and facial asymmetry with left sided frontal and parietal prominence, anterior and posterior fontanelle were closed. Sagittal and right coronal sutures were fused suggestive of craniosynostosis. (e–g) Case III showing mild facial asymmetry with the hypoplasia of the right side of the face. He had medially flared eyebrows; right sided microtia; bilateral ear pits; long, deep and grooved philtrum; high arched palate and bulbous nose.

Figure 2. (a) Karyotype analysis of case I showing a marker chromosome (47,XY,+mar) and (b) mother showing balanced translo- cation carrier between chromosomes 11 and 22. ultrasound abdomen and magnetic resonance imaging mother was found having balanced translocation carrier (MRI) of the brain were also normal. Karyotype analysis between chromosomes 11 and 22 (figure 2b). showed the presence of a marker chromosome (figure 2a) Case II is a 10 month old female child, referred for eval- and cytogenetic microarray showed gain of 18 Mb on uation of facial dysmorphism and global developmental and gain of 3.4 Mb on chromosome 22 delay, previously reported in clinical genetics (Agarwal (figure 3). Karyotype of the parents was done and the et al. 2013). She had partial neck control, could turn from 208 Deepti Saxena et al.

Figure 3. (a) Cytogenetic microarray showed gain of 18Mb on chromosome 11 ([arr[hg19] 11q24.2q25(116,681,007–134,938,470)X3) in case 1 and 18 Mb gain of chromosomal 11 [arr[hg19]11q23.3q25(116,701,058–134,926,021)X3] in case 2. (b) Heterozygous gain of 3.4 Mb on chromosome 22 [arr[hg19] 22q11.1q11.21(16,888,899–20,311,858)X3] in case 1 and 3.6 Mb gain at chromosome 22 [arr[hg19]22q11.1q11.21(17,073,889–20,729,506)X3] in case 2. Case series of Emanuel syndrome 209

Figure 4. (a) Karyotype of case II showing marker chromosome, 47,XX,+mar. (b) Case III showing presence of marker chro- mosome (47,XY+mar) and (c) mother of cases III showed apparently balanced translocation between chromosomes 11 and 22 [46,XX,t(11;22)(q25;q13)]. supine to prone position but not vice versa and could sit was born at term by Cesarean section with no history with support. She was born to nonconsanguineous par- of any adverse perinatal event. He achieved partial head ents with a normal antenatal and perinatal period. On control and occasional social smile in 8 months. He was examination, her head circumference was 38 cm (–3.5 SD), the first child of nonconsanguineous parents. On exam- weight was 5 kg (< 3rd centile) and length was 60 cm ination, his length was 67 cm (10th centile), weight was (< 3rd centile). She had gross cranial and facial asymmetry 7.6 kg (10th centile) and head circumference was 43 cm with left sided frontal and parietal prominence. Anterior (10th centile). He had mild facial asymmetry with hypopla- and posterior fontanelle was closed. Sagittal and right sia of right side of the face. He had sparse and medially coronal sutures were fused suggestive of craniosynostosis. flared eyebrows with normal hair, downward slanting Bilateral proptosis was present (figure 1, c&d). She had eyes, right sided microtia, bilateral ear pits; long, deep sparse eyebrows with normal hair. Other dysmorphic fea- and grooved philtrum; high arched palate and bulbous tures include downward slanting eyes and preauricular tag. nose (figure 1, e, f&g, photograph taken at 4 years). He Genitalia and rest of the systemic examination were unre- had three café-au-lait spots, 1–2 cm in size present over markable. Echocardiography, ultrasound abdomen and his chest, right buttock and back. Eye examination was eye were normal. CT scan showed right coronal suture normal. Brainstem evoked response audiometry (BERA) fusion. Her karyotype also showed the presence of marker showed bilateral hearing loss. Atrial septal defect (ostium chromosome (figure 4a). Fluorescence in situ hybridization secundum type – 11 mm) with left to right shunt was was done to ascertain the origin of marker chromosome, found on echocardiography. Computed tomography scan was suggestive of 22q11.2 trisomy.Cytogenetic microarray of temporal bone showed absence of right external ear revealed 18 Mb gain of chromosomal 11 and 3.6 Mb gain at canal with small opacified middle ear ossicles. Chromoso- chromosome 22 (figure 3). Karyotype of parents revealed mal analysis showed the presence of marker chromosome that her mother having balanced translocation between (figure 4b). Karyotype of the mother showed apparently chromosomes 11 and 22 [46,XX,t(11;22)(q25;q13.1)]. balanced translocation between chromosomes 11 and 22 Case III is a 8 month old male infant with chief [46,XX,t(11;22)(q25;q13)] (figure 4c). complaint of feeding difficulty, developmental delay, ear Case IV is a 6 year old female child who presented deformity and recurrent respiratory tract infections. He with delayed attainment of milestones. She was born to 210 Deepti Saxena et al. nonconsanguineous parents. During the antenatal period, malformations have also been found to be associated with her mother was diagnosed to have oligohydramnios. She this syndrome with an incidence ranging from 19 to 36% by was delivered by Caesarean section at 8 months in view different groups (Fraccaro et al. 1980; Carter et al. 2009). of foetal distress with a birth weight of 1.8 kg. She had Ultrasonography (USG) for renal malformation was done history of feeding difficulty after birth and was diag- in two cases and did not show any renal malformation. The nosed to have cleft palate, for which she got operated at incidence of central nervous system (CNS) abnormalities around 14 months age. At six months of age, she had has not been studied much. Pallotta et al. (1996) reported an episode of febrile seizure during which she was diag- CNS anomalies in 30% of the patients, the abnormalities nosed to have atrial septal defect. She attained head control reported were Dandy–Walker malformation, hypoplastic in 8 months, started sitting with support in 2 years and corpus callosum and ventriculomegaly. In this study, only standing with support in 4 years. She started speaking one patient had hypoplastic corpus callosum. bisyllables at 2 years of age but could not speak sen- One of our patients had unilateral microtia. Glaser et al. tences. She was not toilet trained. On examination, her (2013) have described a case with bilateral microtia and weight was 14 kg (–3 SD), height was 108 cm (10th centile) had overlapping features of Goldenhar and Emanuel syn- and head circumference was 47 cm (< 3rd centile). Facial drome. Cleft palate was present in one of our patients, and dysmorphism included downward slanting eyes, sparse it was found in 54% of patients in a study by Carter et al. eyebrows, bilateral preauricular skin tags and right preau- (2009). Genital abnormalities including cryptorchidism ricular pit. Hands, feet and genitals were normal and the and small penis, which have been reported in 45–65% of rest of the systemic examination was unremarkable. MRI males was not found in our patients. Unilateral craniosyn- brain showed hypoplastic corpus callosum. The karyotype ostosis, which was present in one of our case had not been was 47,XX,+der(22),t(11;22) and that of the mother was reported earlier in association with this syndrome. It may 46,XX,inv(9),t(11;22) which was consistent with the diag- be a rare manifestation of this disorder. Similar is the case nosis of Emanuel syndrome. with facial asymmetry and café-au-lait spots seen in case III of this series. Cat eye syndrome is an important differ- ential diagnosis, but developmental delay is mild and iris Discussion coloboma is a hallmark feature (Rosias et al. 2009). The diagnosis of Emanuel syndrome can be made on Emanuel syndrome is a rare chromosomal disorder char- the basis of presence of characteristic clinical features and acterized by global developmental delay, , fail- sSMC, i.e. derivative chromosome 22 on chromosomal ure to thrive, facial dysmorphism, cleft palate or high analysis. Around 9% of all SMCs arise from chromo- arched palate, heart defects, genital and renal abnormal- some 22 (Crolla et al. 2005). In around 99% of cases, ities. It is characterized by the presence of a supernu- the extra derivative chromosome 22 arises during 3:1 mei- merary derivative 22 chromosome. The exact incidence otic segregation in one of the parents who is a carrier is unknown. However, more than 100 cases have been of apparently balanced translocation between chromo- reported in the literature. Dysmorphic features com- somes 11 and 22. The origin of marker chromosome prise microcephaly, downward slanting palpebral fissures, found on karyotyping can be ascertained by a variety of prominent forehead, long philtrum, microretrognathia, techniques including multiplex ligation-dependent probe and ear anomalies. The most common ear abnormality is amplification (MLPA), FISH and cytogenetic microarray preauricular pit which is seen in 76% of patients (Kapoor (Vorstman et al. 2006). The t(11;22), translocation is the et al. 2015). This was seen in all our cases. Only one of this most common recurrent non-Robertsonian translocation series had microcephaly.Developmental delay was the pre- in humans (Fraccaro et al. 1980) due to the fact that palin- senting feature in all our cases and was the main reason for dromic AT-rich sequences surround the break points in medical attention. Three of four cases were diagnosed in chromosomes 11 and 22 which predicts the formation of infancy due to parental concerns regarding developmen- a hairpin or cruciform structures (Kurahashi et al. 2001). tal delay and presence of facial dysmorphism. In a study These unstable DNA structures in 22q11 and 11q23 facil- conducted by Carter et al. (2009), 78% of patients were itate the recurrent t(11;22) translocation. The breakpoints diagnosed within first year of their life. There is history of of this rearrangement in different families are found to be feeding difficulty in three of four cases. Downward slanting located in closely clustered regions. The two cases studied eyes and ear abnormality were present in all of our cases. by microarray supported the breakpoints on chromosome Ear anomalies ranging from preauricular pit or 11 were within 20 kb distances and those on the chromo- to microtia were present. Two of four patients had microg- some 22 varied by a distance of about 180 to 400 Kb. The nathia and frontal prominence. risk of recurrence depends on whether the chromosomal Structural heart defects were found in 57% of cases in abnormality in the proband is inherited or de novo. Kary- astudybyCarter et al. (2009) and in 62% of cases by otyping of the parents is essential to provide the exact risk Lin et al. (1986). In this case series, two of four cases had of recurrence and genetic counselling to the family. The a heart defect (50%), namely atrial septal defect. Renal risk of recurrence to sibs is 3.7% if a mother is found to Case series of Emanuel syndrome 211 be a carrier, whereas it is 0.7% if the father is having the Fraccaro M., Lindsten J., Ford C. E. and Iselius L. 1980 The translocation (Hou 2003). 11q;22q translocation: a European collaborative analysis of In conclusion, although it is a rare condition, careful sys- 43 cases. Hum. Genet. 56, 21–51. Glaser T. S., Rauen K. A., Jeng L. J. and de Alba Campomanes temic examination with a high index of suspicion would A. G. 2013 Lipodermoid in a patient with Emanuel syndrome. help in early diagnosis. This will not only assist in better J. AAPOS. 17, 211–213. management of the patient but will also help in prena- Hou J. W. 2003 Supernumerary chromosome marker tal diagnosis in next pregnancy. Moreover, carrier testing der(22)t(11;22) resulting from a maternal balanced transloca- can be offered to the unaffected siblings of the carrier tion. Chang Gung Med. J. 26, 48–52. 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Corresponding editor: Dhavendra Kumar