Clinical characteristics.

Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties. Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life. Rare findings may include seizures with onset in later childhood and conductive hearing loss.

Diagnosis/testing.

The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in ODC1 identified by molecular genetic testing. Heterozygous pathogenic variants in ODC1 that cause BABS are typically gain-of-function variants.

Management.

Treatment of manifestations: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.

Surveillance: Measurement of growth parameters, evaluation of nutritional status and safety of oral intake, monitoring for signs and symptoms of constipation, assessment of mobility and self-help skills, monitoring of developmental progress and educational needs, and assessment for new manifestations (seizures, changes in tone) at each visit. Complete skin evaluation for follicular cysts at least annually. Behavioral assessment for signs of autism spectrum disorder, attention, and aggressive or self-injurious behaviors annually. Ophthalmology and audiology evaluations annually or as clinically indicated.

Therapies under investigation: An experimental targeted treatment with difluoromethylornithine (DFMO) is being explored on a compassionate use basis; it is not currently an FDA-approved treatment for BABS.

Genetic counseling.

BABS is expressed in an autosomal dominant manner and typically caused by a de novo ODC1 pathogenic variant. Therefore, the risk to other family members is presumed to be low. Once an ODC1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

BABS should be considered in individuals with the following clinical, suggestive laboratory, and imaging findings.

Clinical findings

• Prenatal history of polyhydramnios
• An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth with congenitally absent or sparse eyebrows and eyelashes
• Developmental delay, typically in the moderate to severe range
• Hypotonia
• Macrocephaly, defined as OFC of >97^th percentile for age and sex
• Macrosomia (defined as weight and length >95^th percentile for age and sex) in early infancy
• Recurrent follicular cysts

Suggestive laboratory findings. Metabolomic profile showing abnormal polyamine pathway metabolites, including increased N-acetylputrescine

Brain MRI findings

• Nonspecific white matter hyperintensities
• Cystic lesions, primarily in the periventricular region but occasionally in other areas, potentially associated with in utero intraventricular hemorrhage

Establishing the Diagnosis

The diagnosis of BABS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ODC1 identified by molecular genetic testing (see Table 1 and Molecular Genetics).

NOTE: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to pathogenic variants in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous ODC1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. (3) Heterozygous pathogenic variants in ODC1 that cause BABS are typically gain-of-function variants (see Molecular Genetics).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of BABS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, nine individuals from nine families have been reported with a pathogenic variant in ODC1 [Bupp et al 2018, Rodan et al 2018, Rajasekaran et al 2021, VanSickle et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Alopecia appears to be the most distinctive feature of BABS, but it does have some variability.

• Hair is typically present at birth but is sometimes sparse and sometimes has atypical color (darker or lighter than anticipated).
• Loss of hair, if present, begins in the first few weeks of life with hair falling out in large clumps.
• Absent or sparse eyebrows and eyelashes are typically congenital.
• Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes.

Nonspecific dysmorphic features. Dysmorphic features have been identified in most affected individuals, but not with any discernible pattern or consistency.

Developmental delay / intellectual disability. Developmental delay is evident early in life with both motor and speech delays. Walking was achieved between age 17 months and four years, although two affected individuals still had not walked when reported at ages three and five years. First words were said between ages three and six years; three affected individuals were nonverbal when reported at ages ten months, 32 months, and 16 years.

Hypotonia is uniform and likely contributes to motor developmental delay.

Behavior. Attention-deficit/hyperactivity disorder (ADHD), autism, and aggression have all been reported in five of the nine published individuals.

• Behavioral concerns evolved in one affected individual treated with difluoromethylornithine (DFMO) (see Therapies Under Investigation), resulting in a diagnosis of autism.
• It is unclear whether DFMO treatment accelerated the development of autistic symptoms that would have developed in any case (although more slowly) without treatment, or whether the treatment itself affected brain function through the alteration of polyamine levels.

Growth. Larger head circumference for age and sex is often seen. One affected individual with a normal head circumference had sagittal craniosynostosis, which has not been seen in any other reported individuals.

Macrosomia at birth has been reported; in four of five affected individuals measured, length was >95% percentile, and in two of five weight was >95% percentile. However, growth parameters tend to normalize with age: at later childhood examination, only two of eight had height >95% percentile and none had weight >95% percentile.

Gastrointestinal and feeding. Ability to feed varies with developmental level, with some affected individuals requiring gastrostomy tube. Others can take food by mouth. Constipation has been seen and may be related to hypotonia.

Skin findings including keratosis pilaris, recurrent follicular cysts (particularly on the back, axilla, and posterior of head), and dry skin have been observed in childhood. Cysts were noted in the first few years of life and resolved with DFMO treatment (see Therapies Under Investigation).

Seizures are seen in one individual, at age 23 years the oldest known with BABS. His seizures emerged at age 14 years, and multiple seizure types have been observed including atypical absence, atonic, and generalized tonic-clonic. Treatment has been challenging as no controlling medication has been identified [VanSickle et al 2021].

Brain MRI findings. Abnormalities identified on brain MRI vary quite broadly without a unifying pattern, although cystic lesions have been reported, and nonspecific white matter changes (loss, hyperintensity, signal abnormality) have been observed in six of nine affected individuals.

Other. Because this is a newly recognized condition, it is unclear if the following findings are associated with BABS or represent rare co-occurrences, as the findings have been found in a small number of affected individuals.

• Hearing loss. One individual had unilateral congenital sensorineural hearing loss. Three individuals have required myringotomy.
• Congenital heart disease. Mild pulmonary stenosis has been reported in one affected individual and ventricular septal defect (self-resolved) was reported in another.
• Nail anomalies. Two affected individuals had brittle nails and another had hypoplastic toenails.
• Ophthalmologic findings. One reported individual had esotropia, pseudostrabismus, and bilateral myopic astigmatism.

Prognosis. The availability of experimental targeted treatment options (see Table 7) may change the natural history of this condition. It is unclear if diagnosis prior to symptom onset, coupled with targeted therapies, will decrease the morbidity and mortality of this condition in the future.

Genotype-Phenotype Correlations

Gain-of-function variants located in the C terminus are associated with BABS. For example, pathogenic variants resulting in a premature termination codon within the last exon, escaping nonsense-mediated decay and causing a gain-of-function terminus, are associated with BABS.

Loss-of-function variants may be enriched with neurologic phenotypes (see Genetically Related Disorders).

Nomenclature

Bachmann-Bupp syndrome may also be referred to as ODC1-related neurodevelopmental disorder based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

The prevalence of Bachmann-Bupp syndrome is unknown. Nine affected individuals have been reported in the literature to date. Three additional affected individuals are known to these authors but have not been reported in the medical literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BABS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

An experimental targeted treatment for BABS is being investigated (see Therapies Under Investigation) but is not currently FDA approved for use in this disorder.

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Difluoromethylornithine (DFMO). A compassionate-use protocol investigating the use of this drug in the targeted treatment of individuals with BABS is being used through investigational new drug approval by FDA. Table 7 summarizes the proposed protocol.

Other ODC inhibitors and DFMO analogs with pharmacokinetic profiles superior to DFMO are under investigation. Also, various nature-derived molecules, including allicin and curcumin, are being studied. Finally, polyamine-restricted diets (Nutrialys) that could be of use in lowering the dietary intake of polyamines are being developed. Special tables exist with precise quantities of each polyamine in various foods and drinks, allowing the design of a tailored putrescine-low diet.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Bachmann-Bupp syndrome (BABS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with BABS whose parents have also undergone molecular genetic testing have the disorder as the result of a de novo ODC1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the ODC1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If a parent of the proband is known to have the ODC1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband

• Each child of an individual with BABS has a 50% chance of inheriting the ODC1 pathogenic variant.
• To date, individuals with BABS are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that all probands with BABS reported to date have the disorder as the result of a de novo ODC1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo ODC1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Figure 1.

The polyamine metabolic pathway and associated genetic disorders

ODC and polyamines are intrinsically involved in the regulation of embryogenesis, organogenesis, and tumorigenesis. This occurs through tight regulation of putrescine, spermidine, and spermine, all of which control cell division and proliferation. Spermidine is substrate to eIF5A and essential for its hypusination (activation) and therefore directly affects eIF5A-mediated protein translation events. Many polyamine pathway-linked genes including ODC1, SMS, and DHPS and their gene products (green circles) have recently been identified to cause syndromes with a common finding of global developmental delays in childhood. Other polyamine-associated genes such as DOHH, AMD1, eIF5A, MAT1A/B, MYC, or MYCN may also be involved in similar genetic disorders. Collectively, they represent a new condition, which the authors refer to as polyaminopathy spectrum disorder (PSD).

Figure and legend republished from Schultz et al [2019]

ODC1 codes for ornithine decarboxylase (ODC), a rate-limiting enzyme in the polyamine pathway, converting ornithine into the polyamine metabolite putrescine (see Figure 1). Polyamines (putrescine, spermidine, spermine) are polycationic molecules involved in many physiologic and cell development processes. The C terminus of ODC contains a 37-amino acid region (amino acids 425-461 using the NM_002539.3 transcript) which is functionally important as a destabilization region. In vitro deletions in this region cause a functional ODC protein that is more stable due to reduced proteasomal degradation, resulting in elevated ODC protein and polyamine levels, mainly putrescine and N-acetyl-putrescine.

When intracellular putrescine and other polyamine levels are elevated, these metabolites are acetylated. Acetylated polyamines are shuttled out of the cell in an attempt to regain homeostasis, resulting in elevated plasma N-acetylputrescine. In cell experiments using high-performance liquid chromatography (HPLC), increased putrescine is observed because HPLC is not able to separate putrescine from N-acetylputrescine; however, mass spectrometry does have this capability.

A transgenic mouse model created in 1995 in which a C-terminally deleted ODC (p.Pro427Ter) protein was overexpressed showed higher ODC enzyme levels and increased polyamine metabolites [Megosh et al 1995]. Phenotypically these mice demonstrated skin, nail, and hair follicle abnormalities after birth similar to those seen in humans [Soler et al 1996]. Treatment of the mice with DFMO prevented hair loss and allowed partial regrowth of hair [Soler et al 1996].

Mechanism of disease causation. Gain of function. All pathogenic variants reported to date are in exon 12 (amino acids 414-461 using the NM_002539.3 transcript) or at the intronic splice site before exon 12, resulting in deletion of the C-terminal region.

Cancer and Benign Tumors

Due to its role in regulating cell growth and proliferation, the polyamine pathway and ODC are known to be involved in neoplastic cell growth, specifically in neuroblastoma and in breast, colon, lung, prostate, and skin cancers [Nowotarski et al 2013]. ODC is a transcriptional target of the MYC oncogene, which mediates cell apoptosis, differentiation, metabolism, and proliferation. Therefore, difluoromethylornithine (DFMO) has been studied as a potential treatment for or preventative of neuroblastoma, glioblastoma, and prostate, skin, breast, and colon cancers. While oral DFMO has not yet been FDA approved, it has been approved for other routes of administration, specifically via intravenous administration for trypanosomiasis and topical administration for hirsutism. Oral DFMO has been studied in Phase I/II clinical trials in individuals with neuroblastoma and was found to be safe and well tolerated in the study population through two years of maintenance therapy [Saulnier Sholler et al 2015, Lewis et al 2020].

Author Notes

The Spectrum Health/Michigan State University International Center for Polyamine Disorders (ICPD) is a collaborative translational and clinical research program operated under the auspices of Michigan State University and Spectrum Health West Michigan in Grand Rapids, Michigan. The ICPD launched in summer 2020 and includes a polyaminopathy patient biobank, a state-of-the-art translational research lab core, and a clinical genetics team at Spectrum Health West Michigan. The ICPD offers innovative ways to study polyaminopathies and associated disabilities and to develop strategies for treatment and prevention. This collaborative effort between Spectrum Health and Michigan State University brings world leading experts in the field from the bench and clinic together to study these rare genetic diseases.

www.grc.org/polyamines-conference/2019/

cancer.msu.edu/faculty/bachmann-andre

www.phd.msu.edu/index.php/research/faculty-staff/andre-s-bachmann

Caleb Bupp, MD, FACMG
Division Chief, Medical Genetics and Genomics
Spectrum Health and Helen DeVos Children's Hospital
25 Michigan Street NE, Suite 2000
Grand Rapids, Michigan 49503
[email protected]

André S Bachmann, MS, PHD
Professor of Pediatrics and Associate Chair for Research
Department of Pediatrics and Human Development, College of Human Medicine
Michigan State University
400 Monroe Ave NW
Grand Rapids, Michigan 49503
[email protected].

Research interests: polyamines, ODC, DFMO, natural products drug discovery, proteasome inhibitors, pediatric cancer, neuroblastoma, medical genetics, Bachmann-Bupp syndrome, Synder-Robinson syndrome, preclinical & clinical trial studies

Acknowledgments

The authors acknowledge the research support of the Spectrum Health Michigan State University Alliance Corporation for this work.

The authors would like to thank all individuals with BABS and their families for sharing their medical and personal stories. They are the true experts and based upon their knowledge we have been able to write this GeneReviews chapter.

Revision History

• 25 August 2022 (ma) Review posted live
• 7 January 2022 (cb) Original submission

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