Prenatal Diagnosis Of Hanhart Syndrome

Introduction

Hanhart syndrome (hypoglossia–hypodactyly) is a rare disorder characterised by hypoglossia (a short and incompletely developed tongue), hypodactyly (absent or partially missing fingers or toes), micrognathia (small jaw) and peromelia (malformation of arms and legs). Children do not experience all the symptoms, and the severity of symptoms is different among children. This syndrome belongs to the group of oromandibular-limb hypogenesis syndromes (OLHS).

Although the cases are sporadic, many cases of Hanhart syndrome are seen in consanguineous marriages (marriages between blood relatives), and these parents should be advised to get a pre-natal ultrasound done for the characteristic features seen in this syndrome. This will aid in early diagnosis and the necessary counselling required for the child's parents affected by this condition. The gene responsible for causing this syndrome is unknown; thus, this syndrome can be differentiated from other syndromes by assessing the type and severity of limb and facial malformations.¹

Cause

The cause of this syndrome is unknown, with genetic and environmental factors proposed to contribute to its occurrence. The cases are usually sporadic in unrelated parents where only one parent is affected. Many cases have reported this syndrome in consanguineous marriages, and researchers believe that it could be inherited in an autosomal recessive manner. Thus, compared with unrelated parents, consanguineous parents have an increased chance of carrying the abnormal gene, increasing the risk of children having recessive genetic disorders. Mutation of the homeobox gene Msx2 found in the mesenchyme of branchial arches, developing teeth, limb buds and alveolar ridges has been proposed to contribute to the clinical manifestations.

Some doctors believe that the developmental defect seen in Hanhart syndrome could result from a haemorrhagic lesion or an interruption of the blood supply to the part of the embryo responsible for developing into a tongue, mouth, jaw, arms, legs, hands, feet and part of the brain.

It is theorised that a blood clot formed within a blood vessel could be due to exposure of the embryo to some drugs taken during pregnancy that reduce blood flow through certain organs. Radiation exposure, teratogenic drugs, maternal hyperthermia or chorionic villous sampling procedures are also known to be responsible for this disorder. This rare disorder affects males and females equally.²

Signs and symptoms

Craniofacial abnormalities

• Microstomia (a small mouth)
• Micrognathia (small jaw)
• Hypoglossia (short and incompletely developed tongue)
• Cleft palate and cleft tongue
• Broad nose
• Telecanthus (increase in the distance between the inner corners of the eyelids)
• Facial asymmetry
• Lower eyelid defects
• Mandibular hypodontia (partial absence of jaw)

Limb abnormalities

• Underdeveloped limbs (hypoplasia, which can vary from hypodactyly to adactyly)
• Partially missing or absent fingers and/or toes (ectrodactyly)
• Malformation or partial or complete absence of lower limbs (amelia)

Additional abnormalities

• Some infants may have facial paralysis due to cranial nerve palsy. Many cases exhibit congenital nerve palsy of the 6^th and 7^th cranial nerves. These nerve palsies can worsen the feeding difficulties already experienced due to tongue, mouth or jaw abnormalities.
• Splenogonadal fusion (spleen and gonads fused during foetal development)
• Clubfoot
• a missing kidney
• porencephalic cyst (brain cyst)
• imperforate anus (abnormal location of the anus)
• jejunal atresia (obstruction in the small intestine due to its twisting)
• epicanthus (vertical skin folds that cover the inner corner of the eyes)
• intellectual disability³

Diagnosis

The diagnosis of Hanhart syndrome is usually done at birth and based on a detailed physical examination showing the characteristic features, such as hypodactyly/adactyly, hypoglossia, micrognathia, high-arched palate and inadequate tongue movements.

The pregnancies as a result of consanguineous marriages should undergo a prenatal examination as many cases of Hanhart syndrome are seen in the offspring of these parents. The diagnosis should begin by obtaining a detailed patient history, including a family history of congenital abnormalities, age during pregnancy, reproductive history and medications.

The differential diagnosis should rule out other disorders in the OLHS group, such as Nager syndrome, Goldenhar syndrome, and other acrofacial dysostosis conditions, by differentiating the characteristic facial and limb abnormalities observed in these syndromes.⁹ A genetic analysis can also help rule out syndromes where the genetic cause is known.¹

Prenatal diagnosis

There are no studies documenting a prenatal diagnosis of Hanhart syndrome. Here we focus on the three features that are essential for the diagnosis of this syndrome and how these features can be identified prenatally.

Hypoglossia

Currently, the tongue size is subjectively assessed in relation to the structures of the oral cavity. This does not take into consideration that the oral cavity may be of abnormal size, not the tongue. Objective tongue measurements may help distinguish a genuinely pathologically sized tongue from a normal tongue that has been incorrectly assessed as abnormal. A study conducted foetal tongue measurements in low-risk, well-dated and singleton pregnancies from 13 to 40 weeks of gestation using ultrasound, and high-quality images were obtained. Tongue length, width, circumference and area were measured for each gestational week and the correlation between the tongue size and gestational age was determined. These charts were used to identify cases of macroglossia, microglossia, Pierre-Robin sequence and persistent buccopharyngeal membrane. These charts can find clinical application in identifying syndromes associated with hypoglossia.⁴

Hypodactyly/limb abnormalities

Congenital hand deformities occur in the 4-8 weeks following fertilisation; thus, first-trimester screening can be performed as early as 9 weeks via transvaginal ultrasound. Ultrasound examination evaluates the foetal position, as well as upper arms, forearms, hands, thighs, calves, feet and the number of fingers and toes. If a definitive diagnosis of the abnormalities is made in the first trimester, abortion is recommended.

In cases of suspicious foetal limb abnormalities, a second-trimester ultrasound is recommended. A foetal anomaly ultrasonography performed at 18-22 weeks gestation can detect hand deformities. If severe limb deformities are observed, the patient is advised to terminate the pregnancy. Unfortunately, in many low- and middle-income countries, ante-natal care begins in the third trimester, making hand and digit deformities difficult to detect owing to foetal attitude and decreasing amniotic fluid volume with increasing gestational age.  For those who face the difficult decision to terminate a pregnancy, help and support can be found here.

Another study used 3D ultrasonography in conjunction with 2D ultrasonography to identify complex abnormalities, particularly those involving the hands and feet. A layperson can easily understand 3D ultrasonography results and is useful while counselling parents on the identified anomalies.^5,6,7

Micrognathia

Prenatal diagnosis of micrognathia is crucial to prevent respiratory and feeding difficulties as micrognathia is usually accompanied by upper airway obstruction, glossoptosis and retrognathia.

Midsagittal ultrasound imaging of the facial profile, without any definitive ways of standardising them, was used for the identification of micrognathia, leading to a reduction in sensitivity. For improved sensitivity, objective methods, such as inferior facial angle (IFA), jaw index and fronto-naso-mental angle (FNMA), have been introduced to better characterise micrognathia. In one study, of the 30 biometric parameters associated with the mandible measurement via ultrasound or magnetic resonance imaging for screening micrognathia, 15 provide the warning value or diagnostic criteria for micrognathia during pre-natal examination, which are mentioned below:

• IFA <50° (diagnostic criteria)
• FNMA <135.91° ( diagnostic criteria)
• Maxilla-nasion-mandible angle (MNMA) > 14.20°(warning value)
• Facial maxillary angle (FMA) < 66°(diagnostic criteria) and an FMA <75° (warning value)
• Mandibular protrusion < 66.65° (diagnostic criteria)
• Anteroposterior diameter (APD)/transverse diameter (TD) <0.45 and jaw index of <24 (diagnostic criteria)
• Mandible width (MDW)/maxilla width (MXW) <0.785 (diagnostic criteria)
• Maxillary/mandibular corpus length > 0.0558 (diagnostic criteria)
• Chin/philtrum length < 2.06 (diagnostic criteria)
• Mid-facial/lower-facial depth > 1.01 (diagnostic criteria)
• Maxillary/mandibular curvature > 1.03 (diagnostic criteria)
• Negative foetal profile line (warning value)
• Absence of mandibular gap (warning value)⁸

Collaborative antenatal care and initial management

Antenatal care (ANC) should commence before 10 weeks gestational age. A foetal scan by a skilled and certified sonologist along with a chromosomal anomaly screening should be performed between the 11^th and 13^th week. If a foetal anomaly is observed, it helps in risk categorisation, and referral of high-risk cases to an appropriate facility.

The second-trimester scan should be performed by a sonologist who also specialises in foetal-maternal medicine for high detection rates of foetal anomalies. If a severe anomaly is detected, parents can be advised to terminate the pregnancy.

If a high-risk anomaly is confirmed, parents should be adequately counselled and provided the opportunity for further assessment of the abnormality to enhance their involvement in the care of their child and accept the outcomes.

The management of foetal anomalies involves a multi-disciplinary approach and includes a geneticist for pre- and postnatal genetic counselling; a neonatologist to perform a thorough physical examination of the infant to identify other anomalies; a surgeon to plan surgical reconstruction; a psychologist to provide mental and emotional support and an occupational therapist to improve hand dexterity in case of limb abnormalities.⁵

Steps for efficient ante-natal care

• Every pregnant woman should be advised of the 18–22 weeks ultrasound scan to detect any foetal structural anomalies
• Currently, the number of foetal-maternal medicine specialists in low- and middle-income countries is low and they are expensive. Thus, it is important to provide training to personnel in foetal-maternal medicine to increase the number of specialists in the field
• The problem of increasing medical indemnity costs should be addressed, which is daunting for clinicians who perform foetus ultrasonographic evaluations
• Doctors managing pregnant women should refer them to a certified sonologist for a structural anomaly ultrasound, and the findings should complement the observations of the obstetrician 
• The patients who show abnormal or suspicious findings or difficult-to-identify abnormalities should be referred to the foetal-maternal clinic without delay⁵

Summary

Hanhart syndrome is a rare congenital disorder that is characterised by an undeveloped tongue, short or absent fingers and/or toes, and micrognathia, along with other limb and jaw abnormalities. The diagnosis is usually done after birth, and there are no studies demonstrating the pre-natal diagnosis of the syndrome. 

The three main features of Hanhart syndrome have been individually assessed using ultrasound and should be implemented for the prenatal diagnosis of this syndrome. It is also essential that healthcare professionals are trained in the identification of foetal anomalies. All pregnant women, particularly those in consanguineous marriages, having a family history of congenital syndromes and in high-risk pregnancies should undergo the foetal anomaly scan at 18–22 weeks. Early detection can help clinicians to counsel parents on the next steps and provide the necessary pre and postnatal support.