Arhinia

Arhinia (nasal agenesis, arhinencephaly, arhinogenesis) is a very rare disorder characterised by the congenital absence of the external nose, nasal cavities, cribriform plate, olfactory bulbs and tracts. Secondary to this, disruption hypertelorism, absence or stenosis of the lacrimal ducts, missing paranasal sinuses, hypoplasia of the maxilla and a high arched palate are present in the majority of cases. Sometimes eye anomalies, ear anomalies, cephaloceles and clefts are present. Arhinia often coexists with holoprosencephaly or Bosma arhinia microphtalmia syndrome but it can also be encountered as an isolated anomaly.

ICD-10: Q30.1 Agenesis and underdevelopment of nose

Arhinia is an extremely rare condition. Since the first published case in 1931¹ about 50 cases have been reported in literature. McGlone reviewed 27 neonatal cases and no sex predominance was found. Associated maternal diabetes was suggested in three cases.²

Because of the limited number of cases the etiology is difficult to elucidate. Abnormal migration of neural crest epithelial cells is a possible explanation. A developmental defect of the nasal placodes or early fusion of the medial nasal processes may be another explanation. Arrest of resorption of the nasal epithelial plugs is also proposed as a possible reason.³ 

When there is arhinia, the frontal processes of the maxilla fuse under the glabella. The cribriform plate (roof of the nasal cavity) is missing. The nasal area is flat and firm on palpation although small ridges, a narrow piriform aperture or rudimentary blind ending nostrils are described.^3,4,5,6 The face has a concave appearance in the profile view. Arhinia is complete in most cases, but it can also be partial (hemi-arhinia.)^7,8,9 The frequent association of hemi-arhinia with holoprosencephaly could indicate that these are in fact cases of cebocephaly (proboscis-like nose.) In cebocephaly, the rudimentary nose is located in the midline. 
Arhinia is usually associated with other facial anomalies, most likely the result of the local disruption, like hypertelorism, absence or stenosis of the lacrimal ducts, missing paranasal sinuses, hypoplasia of the maxilla, a high arched palate and a deficient cupid’s bow. Eye anomalies, ear anomalies, clefts or cephaloceles are not uncommon. Isolated arhinia is sporadic in most cases and genetic aberrations are uncommon. Arhinia was once described in Treacher-Collins syndrome (10) and once in Meckel-Gruber syndrome.¹¹ 

Arhinia is the most constant and sometimes only visible feature in Bosma arhinia microphtalmia syndrome (caused by heterozygous mutation in the SMCHD1 gene on chromosome 18p11) in which hypogonadism also constitutes a major feature.1^2,13 Deviant nasal development may affect gonadotropin-releasing hormone neurons as gonadotropin-releasing hormone neurons are born in the nasal placodes and then migrate along olfactory axon fibers to the brain. Impaired development of these neurons could explain hypogonadotropic hypogonadism in affected individuals.¹⁴

Arhinia coexisting with holoprosencephaly may be considered as a separate group as in arhinia cases without holoprosencephaly other anomalies of the central nervous system are rare (except corpus callosum agenesis). In arhinia with holoprosencephaly partial arhinia, hypotelorism (instead of hypertelorism) and other severe facial anomalies are not unusual^8,9 and genetic aberrations are common.¹⁵

Holoprosencephaly is the most severe frequently associated anomaly. Facial anomalies, like hypertelorism and eye anomalies (microphtalmia, anopthalmia, coloboma, Peter’s anomaly¹⁶) are frequently seen in association with arhinia and sometimes clefts, cephaloceles or ear anomalies (asymmetrical or low set ears.) Arhinia was once reported in association with Treacher-Collins syndrome¹⁰ and once with Meckel-Gruber syndrome.¹¹ Arhinia is the most constant feature in Bosma arhinia microphtalmia syndrome in which hypogonadism also constitutes a major feature.¹² The most frequently associated affected other organ systems are the skeletal system (pectus excavatum, short neck, absent 12th rib, syndactyly, clinodactily, bifid thump, pes equinovarus) and genital system (duplication of vagina, hypospadias, micropenis, cryptorchidism.)¹⁷

Other associated anomalies described in case reports are: corpus callosum hypoplasia/agenesis², intracranial arachnoid cyst¹⁸, single umbilical artery¹⁹, pyloric stenosis²⁰, umbilical hernia²¹, sacral dimple^21,22, café-au-lait spots²², persistent ductus arteriosus.²³ Polyhydramnios is a complication that has been described several times.^{6,17,22, 24}

Most cases are sporadic. However in one family an autosomal recessive pattern¹⁶ and in another family an autosomal dominant pattern with reduced penetrance²³ were reported. Genetic aberrations are uncommon.²⁵ Three cases had an abnormal karyotype: in two cases abnormalities of chromosome 9 were detected (mos46, XX/47, XX+9 (26) and 46, XY,inv(9) (21) and a chromosome 3-12 translocation in one case.²⁷ 

Bosma arhinia is caused by heterozygous mutation in the SMCHD1 gene on chromosome 18p11 and is inherited in an autosomal dominant pattern, with variable expression.¹²

The diagnosis is made on the typically physical characteristics of the face of the fetus. The profile is unusually flat or concave with a missing nose and protruding lips. ^{17,19,24,28,29,30} The nasal bones are usually missing. In the nose mouth view, no nose or nostrils are visible. First trimester diagnosis should be feasible as the nose is already visible at 11 weeks. Arhinia was seen with three-dimensional ultrasound at 13 5/7 weeks in a fetus with alobar holoprosencephaly and trisomy 13.³¹
Although the face, especially the profile, is clearly abnormal, the diagnosis is sometimes missed probably due to the lack of associated anomalies in some cases and the rarity of the malformation. Knowledge of the anomaly and especially a systematic approach of the face will be helpful in detecting the anomaly. 
 

Frontonasal dysplasia, holoprosencephaly, proboscis, amniotic band syndrome or atypical clefts have to be considered in the differential diagnosis of arhinia.

As three-dimensional multiplanar ultrasound is very helpful in identifying exact planes, it can play an important role in evaluating the profile. MRI may be helpful to confirm or better define facial, skull or brain anomalies.²⁴ When arhinia is suspected the patient should be send to an expert centre for an advanced ultrasound examination to rule out associated anomalies and consultation by a geneticist and a plastic surgeon.
 

The prognosis for isolated arhinia is generally good. Airway and feeding difficulties are a major concern in early life. Intelligence is usually normal.
As the lacrimal duct system is incomplete, dacryocystitis, epiphora or persistent crusting may develop. Because the olfactory tracts are missing patients with arhinia have an impaired ability to smell and to taste. Swallowing and speech difficulties are complications of the absent nose cavities, maxillary hypoplasia and unerupted teeth.

When arhinia is part of Bosma syndrome, most children require hormone therapy by a pediatric endocrinologist to go through puberty. The cosmetic result of nasal reconstruction will vary per person. When arhinia is part of the holoprosencephaly spectrum the prognosis is usually very poor.¹⁵ 

Standard obstetric care can be applied. Evaluation of the amniotic fluid volume should be performed as polyhydramnios may develop.^6,17,22,24 There should be a high index of suspicion in diabetes.² 

Delivery in a tertiary center is advisable to manage neonatal respiratory impairment, if present. However airway difficulties can be minimal.^6,32 Feeding via an orogastric tube is usually necessary as simultaneous sucking and breathing is impaired. Further work-up to detect associated anomalies include cardiac, renal and cranial sonography. A CT scan can evaluate choanal atresia and the status of the cribriform plate, detect brain anomalies, evaluate the extent of orbital malformations and is an important tool in planning surgical correction.^2,17,33 MRI of the brain is useful to delineate brain anomalies.¹⁷ Vision and hearing assessment should be performed as well as endocrine investigation to detect possible hypogonadotropic hypogonadism.^2,12   

Because of inadequate lacrimal duct system, drainage surgery or antibiotics to treat dacryocystitis may be necessary.^16,17 Surgical reconstruction will need a multidisciplinary approach. Social and psychological trauma to the parents and the child may demand early reconstruction however this is usually delayed until preschool age.^5,34,35 Silicone prosthesis may be an alternative in older children. Staged reconstruction is usually necessary with final revision surgery of the external nose near adolescence. The missing nasal cavity, missing or unerupted teeth and maxillary hypoplasia make orthodontic and/or speech therapy necessary in most cases. 

Social and psychological implications of this anomaly for the entire family need attention.

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