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Peer Reviewed

Photoclinic

Congenital Arhinia With SMCHD1 Variant

Volume 61 - Issue 12 - December 2021

AUTHORS:
Arianne Maya, BS1 • Luis Seguias, MD2

AFFILIATIONS:
1College of Medicine, University of Florida, Gainesville, Florida
2Department of Pediatrics, UF Health, University of Florida, Jacksonville, Florida

CITATION:
Maya A, Seguias L. Arhinia with SMCHD1 variant. Consultant. 2021;61(12):e31-e33. doi:10.25270/con.2021.03.00019

Received November 4, 2020. Accepted January 15, 2021. Published online March 29, 2021.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Arianne Maya, BS, University of Florida College of Medicine, 1257 Southwest 9th Road, #109, Gainesville, 32601 (ammaya@ufl.edu)

 

A 4-month-old boy was brought to our craniofacial clinic with arhinia, severe protein-calorie malnutrition, tracheostomy tube, gastrostomy tube, dependence on supplemental oxygen, global developmental delay, hypogonadotropic hypogonadism, high arched palate, micropenis, and patent foramen ovale (Figure).

Figure. Our 4-month-old patient with arhinia.

 

History. He was born early term at 37 weeks at 2.825 kg. His mother's pregnancy was complicated by tobacco and marijuana use. The boy was intubated at birth, and a 3.0 uncuffed neonatal flexible tracheostomy tube was placed to secure an airway 5 days later. A gastrostomy tube for enteral feeding was subsequently placed.

Physical examination. At his first visit at age 4 months, he was 60.7 cm long (second percentile), weighed 4.63 kg, had a head circumference of 39.4 cm (< first percentile), and had body mass index of 12.57 kg/m2.

On physical examination, he was alert but had limited social interaction, head lagging, and truncal hypotonia. He had normal external craniofacial features, except for his absent nose, and his palate was highly arched. Microphthalmia was not grossly present, and the patient did not have any vision problems. His genitourinary inspection revealed micropenis, and the right testicle was undescended on palpation (later confirmed by ultrasonography scan).

Diagnostic testing. A maxillofacial computed tomography scan conducted previously at another facility showed the absence of nasal bones, absence of nasal cavity in the expected location of ethmoids and superior nasal cavity, a cavity continuous with the anterior cranial fossa, and absence of the fovea ethmoidalis, cribriform plate, and paranasal sinuses. The radiologists did not comment on the presence or absence of microphthalmia, but all orbital structures were intact.

An ultrasonogram showed that his kidneys were fully developed and were without masses or hydronephrosis. Findings from an endocrinologic laboratory workup led to the diagnosis of hypogonadotropic hypogonadism. He was given intramuscular testosterone cypionate, 25 mg, 3 times a month to increase the size of his penis. The patients’ growth hormone, growth factors, and cortisol levels were all within normal limits, ruling out panhypopituitarism. A whole exome sequencing genetic test revealed a variant of uncertain significance on c.1565G>A (p.Ser522Asn) on the structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) gene that is associated with Bosma arhinia microphthalmia syndrome (BAMS).

Discussion. Congenital arhinia (CA) is an extremely rare embryologic condition characterized by the lack of formation of external and internal nasal structures. There have been fewer than 100 cases of CA reported in the literature, with varying presentations. While some genes are thought to play a role in certain arhinia syndromes, the main pathogenic mechanism has yet to be elucidated.

The incidence of CA is less than 1 in 1 million births, with only about 100 cases reported in the last century from around the world.1,2 CA is typically diagnosed after birth; however, diagnosis of arhinia can be made prenatally with prenatal ultrasound screening. Cases can be documented as early as 22 weeks of gestation.3 Prenatal magnetic resonance imaging has also been used to diagnose arhinia in the second trimester.4 Early diagnosis can be important for the family and their physicians to prepare for future complications.

During embryological development, the nose typically develops between weeks 4 and 10, starting with the formation of the frontonasal prominence during week 4.5 During week 5, ectodermal thickenings form on the frontonasal prominence, called the nasal placodes. The center of each placode deepens into the underlying mesoderm to create nasal pits, while also creating lateral and medial nasal processes.5 The nasal pits deepen to become the nasal cavities, while the medial nasal processes fuse to form the bridge of the nose, the intermaxillary process, and philtrum.5 Olfactory epithelium grows on the roof of each cavity and contains ciliated bipolar neurons that give rise to the olfactory nerve.5 Arhinia is thought to occur when the nasal placodes fail to invaginate and there is premature fusion of the medial nasal prominences. However, the pathophysiology is not fully clear.6,7 As seen in our patient, the philtrum can still be present in cases of arhinia, because fusion of the medial nasal prominences still occurs.8

Through genomic sequencing of patients with CA and their family members, one study found that missense variants on a constrained region of SMCHD1 on chromosome 18p11 may be the main cause of both isolated arhinia and BAMS because of a strongly correlated genotype-phenotype relationship.2 Our patient did not meet BAMS criteria because of a lack of certain microphthalmia, but he did have a heterozygous variant in the SMCHD1 gene, which translated to the replacement of the amino acid serine with asparagine and likely the disruption of protein function.2 The fact that this heterozygous mutation resulted in such a severe phenotype implies autosomal dominance. Notably, the specific variant found in our patient’s genome has not been reported in the literature in individuals with SMCHD1-related conditions, which is likely why it was defined as a variant of uncertain significance.

Some patients have isolated arhinia, while others have multiple congenital anomalies. Patients with BAMS typically have arhinia, microphthalmia, and hypogonadotropic hypogonadism.2 One patient was described to have facial, gastrointestinal, and urogenital malformations.9 Our patient had arhinia with hypogonadotropic hypogonadism as his only other major condition. Increasingly, case reports of arhinia have contributed to our current understanding of gonadotropin-releasing hormone (GnRH) neuron embryology.10 The neurons that produce GnRH have been thought to form in the nasal placode and migrate to the hypothalamus along the olfactory neurons because of an association between congenital anosmia and GnRH deficiency, clinically defined as Kallmann syndrome.10,11 Several genetic variants have been associated with Kallmann syndrome and with a variety of phenotypes, including midline anomalies such as arhinia.11

Kallmann syndrome, however, is not always present in patients with CA, indicating diversity in GnRH neuron formation and migration.11,12 In a study of 80 arhinia cases, 33 patients had hypogonadism.2 A recent study found that all of the 5 male patients with forms of arhinia had GnRH deficiency, whereas 3 of the 6 female patients had spontaneous breast development and 2 female patients had normal menstrual cycles.10 This study showed that GnRH neurons may not actually be dependent on olfactory structures. 10

Arhinia may also be present in patients with holoprosencephaly. Holoprosencephaly occurs when the forebrain fails to separate completely into right and left halves during development and can correlate to a range of facial anomalies.13 These include arrhinencephaly, cebocephaly with hypoplastic nose, and even complete cyclopia.13 The most common chromosomal anomaly associated with holoprosencephaly is trisomy 13, but other genetic associations have also been identified.13 Our patient’s only physical anomaly was arhinia, with no eye or palate involvement and no evidence of holoprosencephaly.

One of the main complications in patients with CA is respiratory distress at birth and required tracheostomy.14-16 Nursing care is extremely important for these patients, because they cannot breathe and eat at the same time. Tracheostomy tubes and gastrostomy tubes are often necessary for a patient with arhinia to obtain adequate nutrition and ventilation.15 Our patient struggled with meeting his nutritional needs and required a gastrostomy tube early on. However, it is important to note that while our patient required intubation at birth, a case report of a patient from Malaysia has challenged the notion of infants being obligate nasal breathers.17 In that case, the patient was able to breathe safely through his mouth for 4 days before an elective tracheostomy was performed.17

Treatment and management. Nasal reconstruction in patients with arhinia still lacks a definitive method. Some surgeons have performed maxillary osteotomies with the creation of a new epithelium-lined nasal cavity.18 Others have performed facial distraction osteogenesis.19 The general consensus is to wait until the child is school-aged to perform reconstructive surgery.18 Overall, management of patients with arhinia is complex and requires a robust team. Our patient has been seen by specialists in plastic surgery, otolaryngology, genetics, gastroenterology, pulmonology, endocrinology, social work, and more, all coordinated by our craniofacial clinic.

Patient outcome. Since his first presentation to our clinic, our patient and his family have followed up many times for well-check and specialty visits. He has also been hospitalized for failure to thrive and respiratory infections. At the most recent visit, he was 14 months old and presented as happy and playful, with gastrostomy and tracheostomy tubes in place. He had delayed communication and verbal language development, expressing himself at the level of a 7- or 8-month-old infant. He had no focal motor deficits and no persistence of primitive reflexes. He had normal tone and was able to pull himself up to stand. His head circumference averaged in the 10th percentile throughout his 14 months, in proportion to his length, which also averaged in the 5th percentile.

Our craniofacial surgical center determined that nasal reconstruction would be performed at age 5 or 6 years, once there is an adequate amount of costal cartilage to use.

References

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