Mandibulofacial dysostosis with microcephaly: a syndrome to remember

Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare condition that causes abnormalities of the head and face. Other major extracranial malformations may also be found. The authors present a case of an MFDM in a 35 weeks newborn with antenatal growth restriction. The patient required resuscitation at birth and was diagnosed with oesophageal atresia with tracheoesophageal fistula at day 1. At physical examination he presented multiple congenital malformations including prominent forehead, plagiocephaly, low-set ears, malformed auricles, hypertelorism, downward-slanting eyes, micrognathia, everted lower lip, short neck, wide-spaced nipples and inguinal hernia. Imaging investigation showed dysplasia of the inner ear with agenesis of the vestibular–cochlear nerves and global cerebral atrophy. Analysis of the EFTUD2 gene revealed that the patient was a heterozygous carrier of a pathogenic mutation (c.831_832del[p.Lys277Asnsf*7]), which has not been previously described. This case illustrates the challenges faced in diagnosing and treating MFDM patients.

Background

Multiple malformation syndromes are a challenge that requires a multidisciplinary team approach in order to ensure optimal therapy for each patient. The identification of the specific syndrome is important for the overall care of the patient and to allow the family to understand the recurrence risk for future pregnancies. As the molecular basis for many syndromes is now better understood, aetiologic identification has become the rule and can be useful even for older patients.¹ In 2006, Guion-Almeida et al described four individuals with a distinct sporadic syndrome, later denominated mandibulofacial dysostosis with microcephaly (MFDM) or mandibulofacial dysostosis type Guion-Almeida.² MFDM is a rare condition (prevalence <1/1 000 000) with an autosomal dominant inheritance pattern. The syndrome has a heterogeneous clinical spectrum. Dysmorphic craniofacial features, microcephaly and malformations of the external and/or middle ear associated with hearing loss are typical. Other manifestations may include oesophageal atresia, congenital heart defects, thumb anomalies and short stature.^{3 4} Haploinsufficiency of EFTUD2 gene, which encodes for a spliceosomal GTPase located at 17q21, is the responsible mechanism for MFDM and was described in 2012.⁵

Case presentation

A male preterm neonate was born by caesarean section at 35 weeks of gestation due to non-reassuring fetal state. His 44-year-old mother had a history of hypothyroidism (treated with levothyroxine), infertility and multiple abdominal surgeries. This was an in vitro fertilisation (IVF) pregnancy with donated oocytes due to diminished ovarian reserve. The pregnancy was complicated with gestational diabetes (treated with metformin), severe pre-eclampsia and intrauterine growth restriction (IUGR). There was no history of consanguinity. The neonate was intubated at birth and the Apgar scores after 1, 5 and 10 min were 4, 7 and 7, respectively. Birth weight was 1440 g (<3rd percentile), length 42 cm (<3rd percentile) and head circumference 30 cm (3rd percentile). At physical examination he presented multiple congenital malformations including: prominent forehead, plagiocephaly, facial asymmetry, hypertelorism, downward-slanting eyes, low-set ears with slightly malformed auricles, everted lower lip, mandibular hypoplasia (micrognathia), short neck, wide-spaced nipples and right inguinal hernia (figures 1 and 2). A diagnosis of oesophageal atresia with tracheoesophageal fistula was made at day 1 and the patient underwent corrective surgery at day 6 (figure 3). No intraoperative or immediate complications were noted. Nevertheless, his clinical condition worsened during hospitalisation. The patient developed bilateral chylothorax requiring treatment with octreotide and chemical pleurodesis. The postoperative course was also complicated with oesophageal stricture requiring endoscopic dilatation, severe gastro-oesophageal reflux and persistent oral feeding incoordination requiring a nasogastric (NG) feeding tube.

Figure 1.

Dysmorphic features presented since birth: facial asymmetry, prominent forehead, hypertelorism, downward-slanting eyes, mandibular hypoplasia (micrognathia), everted lower lip, low-set ears with slightly malformed auricles, short neck, wide-spaced nipples. Left picture taken at 6 months old and right picture taken at 33 months old.

Figure 2.

Low-set ears with malformed auricles: left ear at 6 months old and right ear at 33 months old.

Figure 3.

Posteroanterior chest and abdomen X-ray performed at day 1, confirming the diagnosis of oesophageal atresia (nasogastric tube in the proximal oesophageal pouch). The presence of bowel gas indicates the presence of a tracheoesophageal fistula.

Investigations

Workup was performed to exclude other malformations. Echocardiography revealed a patent foramen ovale and no other structural alterations were identified. Abdominal, pelvic and renal ultrasonography were normal. Serial transfontanellar ultrasound showed enlargement of the pericerebral space by the 10th week of life. Ophthalmologic examination showed slight narrowing of the blood vessels, with no other abnormalities. Auditory brainstem response audiometry revealed bilateral conductive and sensorineural hearing loss (absent waves). CT showed agenesis of vestibular–cochlear nerves, dysplasia of the semicircular canals and ossicular chains bilaterally, and membranous atresia of the left external auditory canal. The brain MRI confirmed reduction of supratentorial encephalic volume compatible with brain atrophy and progressive microcephaly (figure 4); the MRI also revealed a right fronto-parietal subdural collection compatible with chronic subdural haematoma or effusion with elevated proteinaceous content, without mass effect. Skeletal survey was unremarkable. Extended metabolic screen and array comparative genomic hybridisation were normal.

Figure 4.

Brain MRI performed at 6 months old, showing reduction of the supratentorial encephalic volume compatible with atrophy/progressive microcephaly.

The major clinical findings (craniofacial anomalies, hearing loss, microcephaly and oesophageal atresia with tracheoesophageal fistula) lead to the clinical suspicion of MFDM. Analysis of the EFTUD2 gene revealed that the patient was a heterozygous carrier of a pathogenic mutation (c.831_832del[p.Lys277Asnsf*7]), which has not been previously described.^{4 6}

Differential diagnosis

Facial dysostoses describe a group of clinically and aetiologically heterogeneous congenital craniofacial anomalies. These disorders are a consequence of the impaired development of structures derived from the first and second branchial arches. Facial dysostoses can be subdivided into acrofacial dysostoses (AFD) and mandibulofacial dysostoses (MFD).⁷ Treacher Collins syndrome is the best known form of MFD. Affected individuals have craniofacial anomalies with malformations of the outer and middle ear that could resemble MFDM. However microcephaly and intellectual disability are not typical, and cardiac and oesophageal malformations are absent. Lower lid abnormalities are common.^{3 7} Nager syndrome is an AFD with craniofacial malformations, external ear anomalies, conductive deafness and cleft palate, similar to MFDM. Nevertheless, patients have pre-axial limb anomalies which are characteristically variable and often asymmetric. The presence of microcephaly and the genetic testing facilitate the differential diagnosis.⁷

CHARGE syndrome shares some characteristics with MFDM, including choanal atresia, dysplastic ears, facial asymmetry, semicircular canal abnormalities, oesophageal atresia, congenital heart defects and intellectual disability. However, IUGR and microcephaly are uncommon. In addition, patients with CHARGE syndrome usually present with unilateral or bilateral eye abnormalities, namely iris coloboma.^{3 8}

In VACTERL association there are some congenital malformations similar to MFDM, namely vertebral defects, anal atresia, cardiovascular anomalies, tracheoesophageal fistula with or without oesophageal atresia, renal anomalies and limb abnormalities. However, these patients do not typically have neurocognitive impairment, which strongly suggests an alternative diagnosis.⁹ Based on clinical features, our patient was diagnosed with MFDM, which was confirmed with genetic testing.

Treatment

This case demanded a complex therapeutic approach to the several dysfunctions presented by the patient. Due to mandibular hypoplasia, the patient required intubation and mechanical ventilation from birth. The course was complicated with bilateral chylothorax requiring treatment with octreotide and chemical pleurodesis and then with laryngomalacia and bronchomalacia. He was only extubated at day 52. The patient continued to be oxygen-dependent despite improvement in other clinical parameters and was diagnosed with bronchopulmonary dysplasia, and started on inhaled corticotherapy. He was able to self-ventilate in air on day 149. Corrective surgery of the oesophageal atresia with tracheoesophageal fistula was performed at day 6. However, the course was complicated with oesophageal stricture and he underwent three endoscopic dilatations. Gastro-oesophageal reflux was managed with a combination of a proton pump inhibitor and a prokinetic agent. Persistent oral feeding incoordination did not improve with oral motricity stimulation and the patient was discharged home with NG tube feeding. He later underwent gastrostomy. Altogether, these complications required prolonged hospitalisation. He was discharged at a postnatal age of 8 months.

Outcome and follow-up

The patient was referred to a rehabilitation centre and to the outpatient clinics of Developmental Paediatrics, Paediatric Gastroenterology, Pulmonology, Ophthalmology, Otorhinolaryngology and Paediatric surgery. He initiated physical and occupational therapies to stimulate the psychomotor development and speech/language therapy for sensorimotor stimulation. He did not react to sounds, and otoacoustic emissions and automated auditory brainstem responses confirmed hypoacusia. He used hearing aids between the age of 26–32 months, at which point the parents claimed maladaptation and absence of benefit. No auricular reconstruction surgery was performed on the child. The patient developed failure to thrive and severe microcephaly. From the age of 2 years he presents kyphoscoliosis and flat feet and has therefore initiated orthopaedic follow-up. He is currently 33 months old, his weight is at the 25–50th percentile, has a short stature and microcephaly (height and head circumference under the 1st percentile). His global development was delayed. He started holding and transferring objects since 18 months, sitting with support from the age of 2 years, standing with support from 30 months and requires holding on to maintain his stance. He also presents severe language delay. He smiles and vocalises but does not produce recognisable words and does not understand very simple verbal orders.

Discussion

MFDM (MIM# 610536) is a syndrome with multiple malformations and a wide spectrum of clinical features.^{3 4} The condition should be considered when three or more of the five major features are present: (1) mandibulofacial dysostosis, which is most commonly characterised by malar and maxillary hypoplasia, but can also be associated with other anomalies such as midline cleft palate, choanal atresia and/or lacrimal atresia; (2) microcephaly (congenital or progressive) with intellectual disability, which is present in virtually all individuals with variable severity; (3) characteristic malformations of the middle ear (absent or malformed ossicles and semicircular ossicles), or of the external ear (microtia, preauricular tags, hypoplasia of the superior helix and antihelix, auditory canal atresia/stenosis) and typically conductive hearing loss in 75% of the cases; (4) oesophageal atresia/tracheoesophageal fistula, present in around 40% of the affected patients; (5) additional dysmorphic features, including metopic ridge, prominent glabella, facial asymmetry, broad nasal bridge with prominent ridge, large oral aperture and everted lower lip.^{1 3 4} In addition to these frequent findings, other anomalies were described, including cardiac defects (40% of patients), short stature (25% of patients) and mild thumb anomalies (25% of patients). The presence of minor changes in the thumbs leads some authors to classify MFDM as an AFD instead of an MFD.⁷ Other anomalies that affect less than 10% of affected patients include renal anomalies, cryptorchidism, vertebral or rib anomalies, scoliosis/kyphosis, central nervous system abnormalities such as cerebral and/or white matter atrophy, lacrimal system abnormalities and branchial cleft and/or remnant.^{3 4} The diagnosis is confirmed by genetic testing. MFDM is caused by pathogenic variants of the EFTUD2 gene. EFTUD2 is located in 17q21.31 and encodes a spliceosomal GTPase that plays an important role in pre-mRNA splicing.⁵ The majority of the pathogenic variants previously described are de novo (including missense, nonsense, frameshift, splice site and complete or partial gene deletions). Less commonly, there are non-sporadic cases probably resulting from germline mosaicism.^3–5 In our case, the mutation could have arisen de novo or been inherited from a germ cell. Although the father’s phenotype was normal it is possible that the pathogenic variant was inherited from his sperm cells (germline mosaicism). Another possibility is that the mutation was present in the donated oocyte. This is particularly relevant since there is a higher rate of genetic alterations associated with IVF procedures with donated oocytes.¹⁰ Prospective studies should evaluate the role of pre-implantation genetic screening in the future.¹⁰ Although this family does not plan a new pregnancy, genetic counselling would be important as the disease is inherited in an autosomal dominant manner, with most of the affected individuals described with a heterozygous EFTUD2 pathogenic sequence variant or deletion.³

In conclusion, the constellation of clinical findings described should raise the hypothesis of MFDM. Its correct diagnosis is fundamental for the follow-up and prognosis of the patient.

Learning points.

• Recognising the clinical features of mandibulofacial dysostosis with microcephaly is crucial for adequate genetic testing.

• The phenotype of patients with EFTUD2 pathogenic variants is highly variable. The diagnosis should be suspected in individuals with ≥3 of the 5 major features: mandibulofacial dysostosis, progressive microcephaly, characteristic malformations of the middle/outer ear, oesophageal atresia/tracheoesophageal fistula and characteristic dysmorphic features (including micrognathia, prominent glabella, a relatively high nasal root with prominent ridge, everted lower lip and facial asymmetry).

• The pathogenic variant identified in this case had not yet been described, possibly explaining his early and severe clinical manifestations.