Bachmann-Bupp Syndrome

Disease Overview

Bachmann-Bupp syndrome (BABS) is a rare genetic disorder caused by gain-of-function changes (pathogenic variants or mutations) in the ODC1 gene. Affected individuals have a distinctive type of hair loss (alopecia), global developmental delay, low muscle tone (hypotonia), nonspecific abnormal physical characteristics (dysmorphic features) and behavioral abnormalities. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment is aimed at the specific symptoms present in each individual.

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Synonyms

• ODC1 gain-of-function-related neurodevelopmental disorder
• neurodevelopmental disorder with alopecia and brain abnormalities; NEDABA
• BABS

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Signs & Symptoms

There are 9 patients reported in the medical literature with BABS. From their histories, pathogenic variants in the ODC1 gene are thought to be responsible for the following:

• Alopecia – hair is typically present at birth but is sometimes sparse and atypical in color; hair loss in clumps begins in the first few weeks of life; there is typically congenital absence or sparseness of eyebrows and eyelashes; some individuals regrow scalp hair that usually remains sparse.
• Dysmorphic features have been identified in most affected individuals but not with any specific pattern or consistency.
• Moderate to severe global developmental delay – walking was achieved between ages 17 months and 4 years and first words were said between ages 3 and 6 years. Some individuals have not yet achieved these milestones at the time of this report.
• Hypotonia
• Behavior concerns – attention-deficit/hyperactivity disorder, autism spectrum and aggression have all been reported.
• Skin findings – Dry, rough patches and bumps on skin (keratosis pilaris), recurrent follicular cysts and dry skin have been reported.
• Feeding concerns and constipation.
• Large head (macrocephaly) and nonspecific brain MRI findings.
• Too much amniotic fluid during pregnancy (prenatal polyhydramnios).

Other findings reported have been quite variable. One patient has been reported with a history of seizures starting at 14 years of age. One individual has been reported with congenital sensorineural hearing loss in one ear. Two individuals with congenital heart disease – one with mild pulmonary stenosis and the other with self-resolved ventricular septal defect – have been reported. Two individuals with brittle nails and one with underdeveloped (hypoplastic) toenails have been reported. One individual with an inward turned eye (esotropia), eyes that appear to be misaligned (pseudostrabismus) and a vision abnormality related to an overly curved cornea (myopic astigmatism) has been reported.

Due to the small number of identified cases, the young age of reported patients and recent discovery of the condition, there is much yet to learn about the natural history of the disease.

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Causes

BABS is caused by changes (pathogenic variants or mutations) in the ornithine decarboxylase (ODC1) gene that are located at one end of the gene, the C terminus. Genes provide instructions for creating proteins which play a critical role in many bodily functions. Pathogenic variants in the ODC1 gene that cause BABS result in an elevated level of ODC protein followed by an increased conversion of ornithine to putrescine and increased accumulation of putrescine in the cells. These are called gain-of-function pathogenic variants.

The penetrance of pathogenic variants in the ODC1 gene is believed to be 100%, meaning that any person who has a pathogenic change in one copy of their ODC1 gene is expected to develop the associated signs and symptoms. It is unclear whether variations in different portions of the gene or variants resulting in loss-of-function of specific proteins may cause other symptoms.

BABS is inherited in an autosomal dominant pattern. Genetic conditions inherited in a dominant pattern occur when an individual has a pathogenic variant in one of their copies of a particular gene. Thus far, all reported patients whose parents have undergone molecular genetic testing have BABS as the result of a de novo, or new pathogenic variant that was not inherited. Each child of an individual with BABS has a 50% chance of inheriting the ODC1 pathogenic variant. To date, no individuals with BABS have reproduced and many are not yet of reproductive age.

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Affected populations

BABS is a rare disorder that was first reported in the medical literature in 2018. As of November 2022, fewer than 30 affected individuals have been identified with the disorder worldwide. Rare diseases often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of BABS. Comparisons may be useful for a differential diagnosis.

Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental genetic disorder caused by pathogenic variants in the CHD3 gene. SNIBCPS is characterized by developmental delay, macrocephaly, ventriculomegaly, hypotonia and joint laxity.

Woodhouse-Sakati syndrome (WDSKS) is an autosomal recessive genetic condition caused by pathogenic variants in the DCAF17 gene. WDSKS is characterized by alopecia totalis, dystonia, hypogonadism and diabetes mellitus.

Alopecia-intellectual disability syndrome 4 (APMR4) is an autosomal recessive genetic condition cause by pathogenic variants in the LSS gene. APMR4 is characterized by congenital alopecia, developmental delay and epilepsy.

Intellectual developmental disorder with macrocephaly, seizures and speech delay (IDDMSSD) is an autosomal dominant condition caused by pathogenic variants in the PAK1 gene. IDDMSSD is characterized by developmental delay, macrocephaly, seizures and ataxia. There is also absence of hair and skin abnormalities as seen in BABS.

Cowden syndrome is an autosomal dominant genetic condition caused by pathogenic variants in the PTEN gene. Cowden syndrome is characterized by developmental delay, macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules and increased risk for breast, thyroid and endometrial cancers.

Additional disorders that can be mistaken for BABS include ectodermal dysplasias, but these are not typically associated with developmental delay or hypotonia and alopecia is present at birth (congenital) in most ectodermal dysplasias.

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Diagnosis

A diagnosis of BABS is based upon identification of characteristic symptoms and molecular genetic testing that reveals a pathogenic variant in the ODC1 gene. Consensus clinical diagnostic criteria have not been established.

Clinical Testing and Workup

Other tests may be performed to assess specific symptoms. For example, if seizure activity is seen or suspected based on body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. Several patients with BABS have had changes noted on brain MRI, but not with a recurrent pattern of abnormalities.

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Standard Therapies

Treatment
Following initial diagnosis, there are a variety of recommended evaluations. Evaluation with a gastroenterology/nutrition/feeding therapy team helps to investigate aspiration risk, nutritional status and signs of constipation. Developmental assessment is important to determine if early intervention services are needed. Neuropsychiatric evaluation is done to screen for behavior concerns. Ophthalmologic and audiology referrals are done to evaluate for vision or hearing concerns. A referral to a dermatologist is indicated if follicular cysts are present. A referral to a cardiologist is indicated if a heart murmur is present. If there is a concern for seizures, a neurologic evaluation with consideration of EEG might be recommended.

The treatment of BABS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Primary care physicians, geneticists, neurologists and other healthcare professionals may need to systematically and comprehensively plan treatment.

Genetic counseling is recommended for families who have a child with BABS.

Psychosocial support for the entire family is essential as well.

Individuals with BABS are recommended to receive the following surveillance at each visit:

• Measurement of growth parameters
• Evaluation of nutritional status and safety of eating by mouth
• Constipation monitoring
• Assessment of mobility and self-help skills
• Developmental progress and educational needs evaluation
• Monitoring for new neurologic manifestations such as seizures and changes in tone
• Assessment of family needs for support and care coordination

Additionally, annual behavioral assessments, ophthalmology and audiology evaluations and skin checks for follicular cysts are recommended.

Affected children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including specialized learning programs may be necessary.

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Clinical Trials and Studies

Under an investigational new drug approval through the FDA, a compassionate-use protocol is investigating the use of difluoromethylornithine (DFMO, also known as eflornithine) in the treatment of individuals with BABS through the International Center for Polyamine Disorders.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Afrin A, Afshan TS, VanSickle EA, Michael J, Laarman RL, Bupp CP. Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment. Pediatr Dermatol. 2022 Nov 28. doi: 10.1111/pde.15187. Epub ahead of print.

Prokop JW, Bupp CP, Frisch A, Bilinovich SM, Campbell DB, Vogt D, Schultz CR, Uhl KL, VanSickle E, Rajasekaran S, Bachmann AS. Emerging role of ODC1 in neurodevelopmental disorders and brain development. Genes (Basel). 2021;12:470

Rajasekaran S, Bupp CP, Leimanis M, Shukla A, Russell C, Gleason E, VanSickle E, Edgerly Y, Wittman B, Prokop JW, Bachmann AS. Repurposing a pre-existing drug to treat a rare disease: Eflornithine used in a patient with ODC1 gain-of-function variant. eLife. 2021;10:e67097

VanSickle EA, Michael J, Bachmann AS, Rajasekaran S, Prokop JW, Kuzniecky R, Hofstede FC, Steindl K, Rauch A, Lipson MH, Bupp CP. Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome. Am J Med Genet A. 2021;185:3485–93.

Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochem J. 2019;476:2047–57.

Bupp CP, Schultz CR, Uhl KL, Rajasekaran S, Bachmann AS. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am J Med Genet A. 2018;176:2548–53

Rodan LH, Anyane-Yeboa K, Chong K, Klein Wassink-Ruiter JS, Wilson A, Smith L, Kothare SV, Rajabi F, Blaser S, Ni M, DeBerardinis RJ, Poduri A, Berry GT. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am J Med Genet A. 2018;176:2554–60.

Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33.

INTERNET

Bupp C, Michael J, VanSickle E, et al. Bachmann-Bupp Syndrome. 2022 Aug 25. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK583220/ Accessed Jan 5, 2023.

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