How to Cite this Article: Jenkinson EM, Kingston H, Urquhart J, Khan N, Melville A, Swinton M, Crow YJ, Davis JRE, Trump D, Newman WG. 2011. Newly recognized recessive syndrome characterized by dysmorphic features, hypogonadotropic hypogonadism, severe microcephaly, and sensorineural hearing loss maps to 3p21.3. Am J Med Genet Part A 155: 2910–2915.
We describe four members of a multiply consanguineous family of British Pakistani origin affected by a newly recognized syndrome characterized by hypogonadotropic hypogonadism, severe microcephaly, bilateral sensorineural hearing loss, moderate learning disability, and characteristic facial dysmorphic features including convex nasal ridge, highly arched eyebrows, hypertelorism, and micrognathia. Although many genes have been identified that underlie both syndromic and non-syndromic forms of sensorineural hearing loss [Petit and Richardson, 2009], congenital microcephaly [Kaindl et al., 2010], hypogonadotropic hypogonadism [Topaloglu and Kotan, 2010], and learning disability [Ropers, 2010], the particular constellation of clinical features reported here has not been described previously.
The proband, patient 1 (Figs. III-3 and 2A) is a 32-year-old male. He has two younger affected sisters (III-8 and III-9) and an affected nephew (IV-2). He was born to consanguineous parents at 37 weeks gestation. Intrauterine growth retardation (IUGR) and oligohydramnios were noted during pregnancy. There had been no known exposure to teratogenic agents. His birth weight was 2.14 kg. He was diagnosed in the newborn period with bilateral sensorineural deafness, had feeding difficulties, and a microcytic hypochromic anemia due to iron deficiency in early childhood (Table I). He demonstrated significant motor developmental delay, walking between 3 and 4 years of age and subsequently had learning difficulties. He had one febrile seizure following immunization in infancy. He had a normal male 46,XY karyotype.
Table I. Table of Clinical Features
OFC, occipitofrontal circumference; SD, standard deviations, IUGR, intrauterine growth retardation; GM, grand mal; NIDDM, non-insulin-dependent diabetes mellitus.
Age at evaluation (years)
Birth weight (kg)
Neonatal feeding problems
Iron deficiency anemia
Diagnosed at 5 yrs
Diagnosed at 1 yr
1 Post-trauma seizure
GM + complex partial seizures from 16 yrs
1 Post-immunization seizure
NIDDM at 30 yrs
NIDDM at 16 yrs
Sprengel shoulder, broad halluces
Stooped posture fifth finger, camptodactyly
Sprengel deformity, genu valgum
Broad thumbs, overlapping toes
Lower limb spasticity
At age 14 years, he presented to the endocrinology clinic with lack of pubertal development, gynecomastia, and atrophic testes. His FSH and LH levels were 0.2 and <0.1 IU/L, respectively (normal ranges 1–11 IU/L and 3–12 IU/L). He had a blunted response to LHRH stimulation testing and was diagnosed with hypogonadotropic hypogonadism. He was noted to have a normal sense of smell.
At 30 years of age, his height was 160.5 cm (−2.1 SD) and his weight 40.6 kg (−3.3 SD). He had severe microcephaly with an OFC of 49.1 cm (−4.6 SD). He had striking dysmorphic features, including a convex nasal ridge, highly arched eyebrows, apparent hypertelorism, micrognathia, and protruding ears with underdeveloped superior antihelix crus (Fig. 2). Ophthalmic examination showed reduced central corneal thickness, myopia, visual field defect, and advanced optic disc cupping with normal intraocular pressures and no retinal abnormalities. Ocular coherence tomography showed thinning of the superior and inferior rims in the right eye and early thinning of the inferior rim in the left eye.
Additional features included a bifid uvula, Sprengel deformity, broad halluces, and psoriasis. He developed non-insulin-dependent diabetes at the age of 30 years and clinical examination showed upper motor neuron signs in his lower limbs, with pes cavus foot deformity, and increased tone and reflexes. Cranial MRI scan at 32 years of age showed several abnormal areas of high signal intensity involving both grey and white matter, most marked in the right parietal and postero-parietal region, but also in the right temporal and left parietal regions, associated with areas of high signal intensity within the periventricular white matter (Fig. 3C).
Patient 2 (Figs. III-8 and 2B) is a 23-year-old female. She was born at 41 weeks gestation after a normal pregnancy with a birth weight of 3.12 kg. She was diagnosed in the newborn period with bilateral sensorineural deafness. She also had early developmental delay, and walked between 3 and 4 years of age.
At age 15 years, she was diagnosed with hypogonadotropic hypogonadism (FSH 0.8 IU/L and LH 0.2 IU/L), due to a lack of pubertal development and primary amenorrhea. She had normal external female genitalia. She shared many of the phenotypic features described in her brother, including facial dysmorphic features, a history of neonatal feeding problems, iron deficiency anemia, moderate learning difficulty, myopia, and a bifid uvula. She also had marked growth retardation, her height was 144.5 cm (−3 SD), weight 36.5 kg (−2.8 SD) and she had severe microcephaly with an OFC of 48 cm (−5.3 SD).
From age 16 years she suffered from generalized motor and complex partial seizures. An EEG demonstrated focal epileptiform activity arising from the left temporal region. Cranial MRI scans at 17 years of age showed multiple high-signal punctuate areas in the grey/white matter interface in the left occipital region and bilaterally in the vertex (Fig. 3A).
When last examined at 23 years of age, she did not have diabetes mellitus, but did have poor balance, stooped posture, hirsuitism, and camptodactyly of the fifth fingers.
Patient 3 (Figs. III-9 and 2C) is a 21-year-old female. She was born at 40 weeks gestation. Oligohydramnios and IUGR were noted during the pregnancy and her birth weight was 2.25 kg. She also had a history of neonatal feeding difficulties and iron deficiency anemia in childhood. She walked for the first time between 4 and 5 years of age. She underwent a radical mastoidectomy of her right ear in early childhood and bilateral sensorineural deafness was first detected at 5 years of age. She had learning disability, speaking only in single words. She had primary amenorrhea with normal external female genitalia. Her FSH and LH levels were 4.8 and 1.3 IU/L respectively, with low estradiol 73 pmol/L (normal range for mid follicular phase 150–650 pmol/L), and low-sex hormone-binding globulin (SHBG) 6 nmol/L (normal range 25–110 nmol/L). Pelvic ultrasound scanning showed a small anteverted uterus with both ovaries present.
She had growth retardation with a height of 135.9 cm (−3 SD), weight 38.5 kg (−3.1 SD) and severe microcephaly with an OFC of 46.8 cm (−6.2 SD). She was also myopic with visual field defects and ophthalmic examination performed under anesthesia showed cupped optic disks, glaucoma, and a grayish retina. Her electroretinogram was normal.
She had additional features, consisting of dental abnormalities (absent roots), Sprengel deformity, and genu valgum. The unusual tooth morphology was noted at age 15 years. Tooth histology was similar to, but not entirely typical of, dentine dysplasia type I. She developed non-insulin-dependent diabetes mellitus at age 16 years. An attempt to undertake cranial MRI scan was unsuccessful. She has had no seizures.
Patient 4 (Figs. IV-2 and D) is an 8-year-old male born to first cousin parents (III-1 and III-2) at 40 weeks gestation. Oligohydramnios and IUGR were noted during pregnancy and his birth weight was 1.9 kg. Sensorineural deafness was detected at 1 year of age. He walked at 2 years. He had many of the phenotypic characteristics present in his affected family members, including neonatal feeding problems, iron deficiency anemia, facial dysmorphic features, and moderate learning difficulties. At 7 years of age, he could speak in three-word sentences. He had a micropenis and cryptorchidism, consistent with hypogonadotropic hypogonadism. Pre-pubertal FSH and LH levels were 0.3 and <0.1 IU/L, respectively, and there was limited response to LHRH stimulation testing. He had growth retardation with a height of 102.8 cm (−3 SD) and weight of 13.06 kg (−3.6 SD), and severe microcephaly with an OFC of 43 cm (−6.3SD). He was also myopic and ophthalmic examination showed grayish retina with normal electroretinogram. There was no evidence of diabetes mellitus, dental, or skeletal abnormalities.
In early childhood he had one seizure following a fall associated with minor head injury. Cranial MRI at 3 years of age showed multiple high signal punctuate areas in subcortical regions and in the deep white matter of the corona radiate, with a large cisterna magna, cerebellar hypoplasia, vermian atrophy, and a small pons, pituitary, and brain stem (Fig. 3B). He developed episodes suggestive of absence seizures aged 8 years of age and EEG demonstrated epileptiform activity in the left hemisphere, maximal in the centro-parietal and parieto-occipital regions.
METHODS AND RESULTS
Ethical approval for this study was obtained from the University of Manchester (06138) and NHS ethics committees (06/Q1406/52). Informed consent was obtained verbally from the three affected adults, who could understand simple explanations of the purpose of the research, with written consent from their parents and the parents of the younger child. The patients were examined by one of the authors (HK) and growth measurements plotted on standard UK growth charts [Freeman et al., 1995]. These do not specifically relate to the Asian population. Affymetrix SNP6.0 array genotyping was undertaken in affected individuals III-3, III-8, III-9, and IV-3 and in two unaffected individuals, II-2 and III-5, as previously described [Daly et al., 2010]. Using AutoSNPa, analysis showed a single large homozygous region of 13.1 Mb on chromosome 3p21.3 (flanked by rs7649806 and rs11130424) shared by affected individuals that encompassed the critical interval containing 227 protein encoding genes [Carr et al., 2006]. Copy number analysis using the CN5 algorithm from Affymetrix defined no variants in the critical region. Sequencing of the candidate TMIE (Transmembrane Inner Ear) gene showed no mutations.
Many recessive forms of non-syndromic sensorineural hearing loss, congenital microcephaly, hypogonadotropic hypogonadism, and learning disability have been defined at a molecular level. However, we are not aware of a previous description of the particular constellation of features observed in the family we report. The features common to all the affected individuals included early feeding problems, moderate short stature, marked microcephaly, moderate learning disability, distinctive facial dysmorphic features, myopia, sensorineural hearing loss, and hypogonadotrophic hypogonadism. Variable features included IUGR and oligohydramnios, iron deficiency anemia, bifid uvula, absent dental roots, later onset non-insulin-dependent diabetes, seizures, and upper motor neuron signs in the lower limbs. In addition, similar, multiple areas of high signal were identified in the cranial MRI scans of the three individuals who had imaging studies.
CHARGE syndrome (OMIM214800), which shows some phenotypic overlap with the features present in the affected individuals in the family described here, is a dominant condition representing a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness). However, the microcephaly described in patients with CHARGE is less severe than seen here, and heterozygous mutations in CHD7 on chromosome 8q12 account for the majority of cases of this condition [Vissers et al., 2004].
In common with the family we describe, children with trichorrhexis nodosa (Pollitt) syndrome (OMIM 275550) can also be affected by hearing loss, microcephaly, hypogonadotropic hypogonadism and developmental delay. However, the individuals we report do not have the brittle hair that is characteristic of that condition [Pollitt et al., 1968].
Woodhouse–Sakati syndrome (WHS) was first described in 1983 in two consanguineous families from Saudi Arabia and is an extrapyramidal syndrome which combines hypogonadism, sensorineural hearing loss, alopecia, diabetes mellitus, and mental retardation (MIM 241080) [Woodhouse and Sakati, 1983]. However, the hypogonadism described in WHS is typically primary. Moreover, there was no evidence of alopecia or cardiac abnormalities in the family described here, reducing the likelihood of WHS. Mutations in DCAF17 on chromosome 2q31 have been identified in patients with that condition [Alazami et al., 2008].
Finally, siblings with microcephaly, short stature, diabetes, gonadal insufficiency, and sensorineural hearing loss have been described [Bangstad et al., 1989]. However, the short stature in those siblings was more pronounced (greater than −7 SD) than in the family described here, the diabetes was insulin resistant, the gonadal insufficiency was primary and they also had progressive ataxia and goiter, which were not features in the current family.
We conclude that the patients we report are affected by a previously unrecognized autosomal recessive syndrome, the causative gene for which maps to a 13.1 Mb locus on 3p21.3. It is possible that the clinical features present in the affected individuals could be due to more than one co-segregating recessive disorder. Furthermore, although autozygosity mapping strategies have been very successful in identifying the causes of autosomal recessive conditions [Daly et al., 2010], cases of compound heterozygous mutations within consanguineous families have been described which limit the effectiveness of this approach and can result in false positive loci [Zlotogora, 2007; Spiegel et al., 2010]. An interesting candidate gene lying within the mapped region on 3p21.3 is TMIE (Transmembrane Inner Ear), mutations in which cause autosomal recessive non-syndromic hearing loss in humans [Naz et al., 2002]. Sequencing of TMIE in the affected individuals reported here showed no pathogenic mutations. Further investigation of the critical interval on 3p21.3 is in progress to define the molecular basis of this novel syndrome.
We thank the Infertility Research Trust (EJ studentship) and the NIHR Manchester Biomedical Research Centre for providing funding to support this work.