Aphonia, microstomia, deafness, retinal dystrophy, duplicated halluces and intellectual disability


  • The authors state there is no conflict of interest.

  • How to Cite this Article: Kariminejad A, Hennekam RCM. 2012. Aphonia, microstomia, deafness, retinal dystrophy, duplicated halluces and intellectual disability. Am J Med Genet Part A 158A: 2756–2762.


We report on a sister and brother born to healthy, double first cousin Iranian parents with a seemingly unique combination of signs and symptoms consisting of intellectual disability, congenital absent voice (aphonia), hearing loss, optic atrophy, retinal dystrophy, mildly broad thumbs, and duplicated halluces. Their facial morphology was unusual: thick eyebrows, ptosis, full eyelashes, long palpebral fissures, downslanting palpebral fissures, small mouth, and low-set, posteriorly rotated ears. This phenotype does not meet the diagnostic criteria of any known entity. Because of parental consanguinity, absence of manifestations in parents, and occurrence in sibs of opposite sex, an autosomal recessive pattern of inheritance is likely. © 2012 Wiley Periodicals, Inc.


Aphonia is defined as the inability to produce speech sounds. Aphonia can be acquired, for instance due to injuries to vocal cords and inflammations or as part of psychiatric disorders, and is only rarely congenital and part of a syndrome.

Here, we describe two siblings with aphonia, distinct facial morphology, optic atrophy, retinal dystrophy, deafness, distal limb anomalies and intellectual disability. This association of findings has not been reported previously, and may constitute an autosomal recessive disorder.


The proband is born to consanguineous parents (inbreeding coefficient 3/32; Fig. 1). Parents are healthy, have a normal phenotype, hearing and vision, and normal cognitive abilities. Family history is otherwise non-contributory.

Figure 1.

Pedigree of family.

The first child is a 5-year-old girl born after an uneventful, term pregnancy. Exposure to possibly teratogenic agents was denied by the parents. Caesarean section was performed because of intra-uterine growth retardation. At birth, weight, length and head circumference were 2,400 g (<3rd centile), 46 cm (3rd centile), and 31 cm (<3rd centile), respectively. She failed to make audible cries at birth or first months thereafter. There were feeding difficulties possibly due to the small mouth. She reached her milestones slowly; sitting at 7 months, crawling at 14 months, and walking at 26 months. Parents noticed hearing loss around 1 year of age. She never achieved the ability to speak or to make varieties of sounds and made low-pitched sounds when crying. Additional studies performed at age 4.5 years included a direct laryngoscopy which showed a narrow larynx with complete paralysis of left vocal cord but normal movements of the right cord. No other anomalies or masses were detected.

Clinical examination at 5 years showed a girl with moderate to severe intellectual delay and marked hearing loss. Height was 95 cm (3rd centile), weight 14 kg (10th centile), and head measurement 44.5 cm (3rd centile). She had an unusual face: full eyebrows, long eyelashes, ptosis, strabismus, long, downslanting palpebral fissures, full cheeks, small mouth but still thick upper and lower vermilions, small and widely spaced teeth, and low-set posteriorly rotated ears (Fig. 2a,c). She also had widely set, inverted nipples, underdeveloped labia majora and minora, tapering fingers, mild broadening of the thumbs, decreased mobility of the distal interphalangeal joints of thumbs and second fingers, and bilateral camptodactyly of fifth fingers (Fig. 3a). The nail of the thumbs were somewhat broad, the other nails were short and narrow (Fig. 4a). The first toes were broad, and right hallux had a valgus position (Fig. 4c). Hand X-rays showed mild broadening of the first ray but otherwise no abnormalities (Fig. 5a). Radiology showed broad first metatarsal bones and inward curving of the distal end, possibly indicating partial duplication, broad and partially delta-shaped proximal first phalanges and almost complete duplication of distal phalanx (Fig. 5c).

Figure 2.

a,b: Note distinctive facial features in siblings including full eyebrows, long eyelashes, ptosis, strabismus, long, downslanting palpebral fissures, microstomia. c,d: Note low-set and posteriorly rotated ears.

Figure 3.

Genitalia. a: Underdeveloped labia majora and labia minora in the proband. b: Bifid and small scrotum encircling the penis (shawl scrotum) in the brother.

Figure 4.

a,b: Tapering fingers, mildly broad thumbs with broad nails, camptodactyly of fifth fingers, and short narrow nails in both siblings. c: Note broad first toe and valgus position in proband. d: Broad feet, partly duplicated halluces, and short distal phalanges of the other toes with small nails in the brother.

Figure 5.

Hand and feet X-rays. a: Proband: mild broadening of the first ray. b: Brother: no visible joint space between the proximal and middle and middle and distal phalanges. c: Proband: broad first metatarsal bones and inward curving of the distal end, possibly indicating partial duplication, broad and partially delta-shaped proximal first phalanges and almost complete duplication of distal phalanx. d: Brother: complete duplication of proximal and distal first phalanges, broad distal first metatarsal bone part of partial duplication, and small distal phalanges of toes 2–5.

Patient 2 was the 5-month-old brother of the proband, born after an uneventful, term pregnancy by caesarean (indicated because of the earlier caesarean). At birth, weight, length, and head circumference were 2,600 g (3rd centile), 48 cm (<10th centile), and 32 cm (<3rd centile), respectively, and at 5 months weight was 6,200 g (10th centile), length was 58 cm (<3rd centile), and head circumference 38 cm (<3rd centile). His facial features were very similar to those in his sister, and included the full eyebrows, long eyelashes, ptosis, long and mildly downslanted palpebral fissures, low-set malformed ears, full cheeks, and small mouth (Fig. 2b,d). He had inverted nipples, small and bifid scrotum that encircled the base of the penis (shawl scrotum; Fig. 3b), tapering fingers, mildly broad thumbs, short and narrow nails, bilateral camptodactyly of fifth fingers and normal mobility of other fingers and thumbs (Fig. 4b). The feet were broad, halluces partly duplicated, and distal phalanges of the other toes, short with small nails (Fig. 4d). Hand X-rays showed no visible joints between the proximal and middle and middle and distal phalanges (Fig. 5b). Feet X-rays showed small distal phalanges of toes 2–5, completely duplicated proximal and distal first phalanges, distal broadening of the first metatarsal bone seemingly as part of partial duplication (Fig. 5d).

Ultrasound examination of abdomen failed to show any organ abnormality. Echocardiography showed a normal heart anatomy. Laboratory examination including white blood cell counts and differentiation, yielded normal results, as did plasma levels of urea, creatinine, electrolytes, calcium metabolism parameters, AST, ALT, thyroid hormone parameters (TSH; T3; T4). Ophthalmic examination in both sibs showed an identical picture: very narrow retinal arteries, no pigmentation disturbances, and optic atrophy, seemingly secondary to the retinal dystrophy (Fig. 6). Electroretinography in the sister showed complete absent responses, confirming the cone and rod dystrophy. There was no myopia. Hearing tests showed bilateral sensorineural hearing loss. Chromosome analysis yielded a normal female and male karyotype, respectively. Whole genome BAC Array CGH (CYTOCHIP genomic bac array version 3.0) failed to show a genomic imbalance exceeding 0.5 MB. As there was phenotypic overlap with Cohen syndrome we sequenced COH1 and no mutations were detected, and at linkage analysis the sibs were found not to be homozygous for the locus either.

Figure 6.

Proband: fundus showing narrow vessels, optic atrophy and retinal dystrophy.


The clinical findings in the present sibs are summarized in Table I, and compared to entities or a case report that show some resemblance. The most distinctive findings are the intellectual disability, facial morphology, hearing loss, retinal dystrophy, broad and (partly) duplicated halluces, and especially the aphonia.

Table I. Comparison of Clinical Features of the Siblings in This Report With Several Syndromes With Some Overlapping Features
 ProbandBrotherCohen syndromeRubinstein–Taybi syndromeOhdo syndrome

Hawkins et al. [1990

  1. +++, 50–100%; ++, 25–50%; +, 1–25%; ±, <1%; –, absent; t.y., too young to be evaluated adequately.

Pretnatal growth retardation++±++
Postnatal growth retardation+++++++++
Truncal obesity+++++
Intellectual disability+++++++++++
Long eyelashes++++++
Full eyebrows++++++
Short nose++++
Nasal septum below alae nasi++++
Aphonia/vocal cord paralysis++±+++
Dental abnormalitiesSmall; widely spacedt.y.Large; prominentTalon cusps; irregular placementSmall
Visual abnormalitiesOptic atrophy; retinal dystrophyOptic atrophy; retinal dystrophyRetinochoroidal dystrophy; myopiaMyopia; progressive ERG anomaliesAmblyopia
Low-set posteriorly rotated ears+++++
Inverted nipples++
Genital abnormalitiesSmall labia majora/minoraSmall scrotum; shawl scrotumCryptorchidismCryptorchidismCryptorchidism
Thumb abnormalitiesBroadBroadBroad; angulatedBroadUnder-developed
Partially duplicated halluces++++
Clinodactyly of fifth fingers+++++++
Small nails++
Tapering fingers+++++
Congenital heart disease±++++
Joint laxity+++++
Intermittent neutropenia+++

Congenital aphonia, either isolated or as part of a syndrome, is infrequent. Congenital vocal cord paralysis is the main cause for aphonia and is usually transmitted in an autosomal dominant way [Gacek, 1976; Mace et al., 1978; Morelli et al., 1980; Brunner and Herrmann, 1982; Grundfast and Milmoe, 1982; Cunningham et al., 1985; Tarin et al., 2005]. Often neonatal stridor and swallowing difficulties are the first manifestations. Linkage of a gene for congenital bilateral adductor paralysis to chromosome 6q16 has been suggested [Mace et al., 1978; Manaligod et al., 2001]. Schinzel et al. [1990] reported laryngeal paralysis and intellectual disability in a brother and two sisters. The parents were healthy with normal intelligence. The mother had unilateral laryngeal abductor paralysis on laryngoscopy and autosomal dominant inheritance was suggested with variable expression, although autosomal recessive with partial manifestation in a heterozygote or X-linked inheritance could not be excluded. X-linked vocal cord paralysis together with intellectual disability has been suggested by some pedigrees [Plott, 1964; Watters and Fitch, 1973]. Some of the patients had more widespread motor disturbances indicating a neuromuscular disorder, either X-linked [Watters and Fitch, 1973] or autosomal recessive [Barbieri et al., 2001]. Koppel et al. [1996] reported a consanguineous family with congenital vocal cord paralysis but normal cognitive development, and also Raza et al. [2002] reported such a family.

Familial cord dysfunction in association with digital anomalies was reported by Hawkins and co-workers in 1990: identical twins were described with bilateral vocal cord dysfunction and camptodactyly of all fingers, their brother had presumed vocal cord paralysis with cutaneous syndactyly of fingers (not further specified), the mother had presumed vocal cord paralysis and small thumbs, a sister of mother had isolated finger camptodactyly, one of her sons had isolated small thumbs, and another son had camptodactyly with presumed vocal cord paralysis. Cognition was normal in all [Hawkins et al., 1990]. There is resemblance to the presently reported sibs but the apparently autosomal dominant pattern of inheritance, absence of unusual facial manifestations, hearing loss and retinal dystrophy, and normal cognition are sufficient to exclude this diagnosis.

Vocal cord dysfunction is only unusually part of multi-systemic syndromes. The main entity to consider is Cohen syndrome. Chandler et al. [2003] described laryngeal abnormalities, vocal cord paralysis, laryngeal stenosis and laryngomalacia in a series of 33 non-Finnish patients with Cohen syndrome. The present patients do show some resemblance to Cohen syndrome (microcephaly, retinal dystrophy, broad eyebrows, full cheeks, intellectual disability) but differ in absence of joint laxity, myopia, open mouth appearance, prominent incisors, obesity, and granulocytopenia, and in the presence of hearing loss, ptosis, small mouth, and broad and duplicated hallux. We cannot exclude the possibility that both sibs have two entities, one being Cohen syndrome and the other being an unknown entity causing the other facial manifestations, deafness, and distal limbs anomalies, but this does not seem likely to occur in two sibs.

If aphonia is not taken as the lead symptom especially the (partly) duplicated halluces have to be taken into account. Patients with Rubinstein–Taybi syndrome show some facial resemblance, but the characteristic facial grimacing when smiling, and typical nasal shape differ [Hennekam, 2006]. Aphonia and microstomia do not occur in Rubinstein–Taybi syndrome, nor does retinal dystrophy [Van Genderen et al., 2000]. Furthermore, although familial occurrence of Rubinstein–Taybi syndrome occurs, it is extremely rare [Hennekam, 2006]. The London Dysmorphology DataBase lists 25 other entities that go along with intellectual disability and duplicated halluces, such as acrocallosal syndrome, Carpenter syndrome, Curry–Jones syndrome, and various types of oral-facial-digital syndrome. Each of these and all others can easily be discarded based on the concomitant manifestations [Hennekam et al., 2010].

The sibs show an overlap in their general facial Gestalt with Ohdo syndrome. Ohdo syndrome (OMIM249620)× is characterized by intellectual disability, congenital heart disease, blepharophimosis, blepharoptosis, and small teeth [Ohdo et al., 1986]. Microstomia, deafness, genital abnormalities, and short stature are additional features of Ohdo syndrome which cause resemblance to the present siblings [Verloes et al., 2006]. The absence of blepharophimosis, congenital heart disease, and small teeth, hallmarks of this syndrome and the presence of aphonia and duplicated halluces argue against this syndrome.

We conclude that the present constellation of signs and symptoms in sibs has not been reported before. The occurrence in a brother and sister, absence of major manifestations in the parents, parental consanguinity, and absence of a detectable chromosome imbalance argue in favor of an autosomal recessive pattern of inheritance. We are currently performing linkage analysis in the family and plan subsequent next generation sequencing in order to try to find the causative gene for this entity.


We thank Dr. Mary J. Van Schooneveld, ophthalmologist, for evaluation of the fundus pictures, Dr. Aldo Jongejan for molecular studies of the COH1 gene and the family for their generous collaboration.