What are the other Names for this Condition? (Also known as/Synonyms)

• Athyroidal Hypothyroidism with Spiky Hair and Cleft Palate
• Bamforth Syndrome
• Hypothyroidism Cleft Palate

What is Bamforth-Lazarus Syndrome? (Definition/Background Information)

• Bamforth-Lazarus Syndrome is a very rare syndrome of congenital hypothyroidism characterized by thyroid dysgenesis (in most cases athyreosis), cleft palate and spiky hair, with or without choanal atresia, and bifid epiglottis. Facial dysmorphism and porencephaly have been reported in isolated cases
• Newborns present at birth with thyroid dysgenesis (in most cases athyreosis) leading to congenital hypothyroidism that manifests with lethargy, poor feeding, macroglossia, cold or mottled skin, persistent jaundice, and umbilical hernia. Neonatal hyperbilirubinemia is also common
• All newborns with Bamforth-Lazarus Syndrome have a cleft palate and spiky hair. Some may also present with choanal atresia and bifid epiglottis
• Facial dysmorphism, consisting of microcephaly, hypertelorism, anteverted nares, narrow nasal bridge, low-set ears, small jaw and retrognathia, has been reported in one case. Porencephaly was also recently described in one case
• Differential diagnoses include other forms of syndromic hypothyroidism such as Johanson-Blizzard syndrome
• The disease is inherited autosomal recessively and genetic counseling is possible. Most of the patients reported to date came from consanguineous parents, both being heterozygous for the genetic mutation. Only 8 patients from 6 families have been reported to date

(Source: Bamforth-Lazarus Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Bamforth-Lazarus Syndrome? (Age and Sex Distribution)

• Bamforth-Lazarus Syndrome is an extremely rare congenital disorder. Fewer than 10 cases have been reported around the world
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Bamforth-Lazarus Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Bamforth-Lazarus Syndrome can be inherited
• Children born to parents who are closely related to each other (by blood) have a high risk for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Bamforth-Lazarus Syndrome? (Etiology)

• Bamforth-Lazarus Syndrome is due to homozygous loss-of-function missense mutations located within the forkhead domain of the FOXE1 gene (9q22), encoding thyroid transcription factor 2 (TTF-2)
• TTF-2 is expressed in the thyroid gland (as well as elsewhere like the tongue, epiglottis and palate) and is thought to play a crucial role in thyroid morphogenesis
• Cases reported so far have all been due to homozygous loss-of-function mutations apart from one case described recently with a novel FOXE1homozygous mutation causing increased thyroid gene expression

(Source: Bamforth-Lazarus Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

What are the Signs and Symptoms of Bamforth-Lazarus Syndrome?

The signs and symptoms of Bamforth-Lazarus Syndrome may include: (Very frequently present symptoms in 80-99% of the cases)

• Abnormal hair quantity
• Choanal atresia
• Congenital hypothyroidism
• Intellectual disability
• Polyhydramnios
• Retrognathia
• Thyroid agenesis
• Bifid epiglottis (in some cases)

(Source: Bamforth-Lazarus Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Bamforth-Lazarus Syndrome Diagnosed?

• The diagnosis of Bamforth-Lazarus Syndrome is based on clinical findings of congenital hypothyroidism with cleft palate and spiky hair along with findings of thyroid ultrasonography (USG) and computed tomography examination
• Thyroid tissue is either completely absent or nonfunctional. Serum thyroid stimulating hormone (TSH) levels should be measured (levels will be elevated on newborn screening filter paper test, as is seen in all cases of athyreosis) to determine necessary treatment dosage
• Molecular genetic testing can identify a mutation in the FOXE1 gene, confirming diagnosis

(Source: Bamforth-Lazarus Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

What are the possible Complications of Bamforth-Lazarus Syndrome?

The complications of Bamforth-Lazarus Syndrome may include:

• Intellectual deficit
• Hormonal imbalances from an early age
• Speech impairment

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Bamforth-Lazarus Syndrome Treated?

• Thyroid hormone replacement therapy is the standard treatment for those with Bamforth-Lazarus Syndrome and should be started as soon as possible. The dosage of synthetic thyroxine (T4) necessary depends on the patient's age, weight and any other medical conditions
• Regular follow up is recommended to monitor any fluctuation in TSH levels and treatment is life-long. In neonates born with hyperbilirubinemia, phototherapy is often effective
• Surgical procedures for cleft palate (maxillo-facial reconstruction and plastic surgery) and choanal atresia (surgery to reopen the nasal passages) should be discussed in a specialized health center. Speech therapy may also be required

(Source: Bamforth-Lazarus Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Bamforth-Lazarus Syndrome be Prevented?

Currently, Bamforth-Lazarus Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Bamforth-Lazarus Syndrome? (Outcomes/Resolutions)

• With proper treatment adherence the prognosis of Bamforth-Lazarus Syndrome is good and children can have normal physical growth, pubertal development, and anterior pituitary function
• Quality of life, however, can be affected by cleft palate/choanal atresia as multiple surgeries may be necessary
• Intellectual development is normal if treatment for hypothyroidism is not delayed

(Source: Bamforth-Lazarus Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Additional and Relevant Useful Information for Bamforth-Lazarus Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/