Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

Fanconi Anemia in the Setting of Multisystemic Abnormalities: A Case Report Dipal Mistry, OMS-III, Kirby Smith, MD Edward Via College of Osteopathic Medicine, Spartanburg, SC

Introduction

Results/Criteria

Conclusions/Implication s

Fanconi anemia (FA) is a rare and progressive congenital bone marrow failure syndrome that is inherited in an autosomal recessive manner in 1 out of 136,000 newborns. However, hematologic anomalies are not the sole manifestations of FA 1 .This multi-systemic disease is characterized by bone marrow failure, congenital malformations, abnormal skin pigmentation, and increased susceptibility to cancers 2 . The classical congenital abnormalities seen in patients with FA include those described in the VACTERL-H (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal atresia, Renal, upper Limb and Hydrocephalus) association. Other abnormalities common to FA were recently grouped with the acronym PHENOS (skin Pigmentation, small Head, small Eyes, Nervous system, Otology, and Short stature). The majority of patients will have at least one abnormality, however between 25-40% of patients with FA will have none, thus the absence of abnormal features does not rule out the diagnosis 1 .The constellation of clinical findings in FA is caused by defects in the ability of the cells to repair damaged DNA, making them hypersensitive to the oxidative stress of DNA-cross linking agents such as Diepoxybutane (DEB) and Mitomycin C (MMC), also known as the Chromosomal Breakage.

• FA often presents initially as thrombocytopenia and/or leukopenia, similar to the present case • Progressive bone marrow failure with pancytopenia typically develops in the first decade of life. Average age of onset is 7.6 years. • Early diagnosis and identification of the patient specific variant is important for the management of these patients, and therefore requires communication between physicians, genetic counselors, cytogeneticists, and hematopathologists 1 . • Main causes of morbidity and mortality in those with FA include aplastic anemia, acute myeloid leukemia, myelodysplastic syndrome, and solid tumor cancers. The highest risk of solid tumor cancers are head and neck squamous cell carcinoma (SCC) and SCC of the anogenital regions. About 20% of patients with FA develop such cancers 2 . Although progressive bone marrow failure is the hallmark of FA, this condition notably presents with a variety of congenital defects. Therefore, a multidisciplinary team is necessary to closely screen for the variety of clinical manifestations of FA: Hematological Managment: All patients with FA should be monitored by a hematologist regardless of the absence or presence of bone marrow involvement. The clinical surveillance and therapeutic management of bone marrow failure is influenced primarily by the severity of the cytopenia(s) and stability of peripheral blood counts 1 . Clinicians are able to gain an understanding on a patient’s severity of bone marrow failure and determine the management of the patient's condition based on labs shown in Table 1. • Stable peripheral blood counts that are no more than mild in severity and have no clonal cytogenetic abnormalities present are monitored every 3-4 months.An annual bone marrow biopsy and aspirate with cytogenetics is recommended. Current case management plan. • Clonal cytogenetic abnormalities and/or unstable peripheral blood counts require immediate evaluation by bone marrow biopsy and aspirate with cytogenetics. Requires ongoing close monitoring with blood counts taken every 1-2 months and bone marrow examination every 3-6 months. Discussion for hematopoietic cell transplant (HCT) is warranted as it is the only curative option for patients with FA. Other options can include packed red blood cell transfusions if the patients’ RBC counts consistently fall below 8 g/d, however transfusions should be limited if the treatment goal is hematopoietic cell transplant 1 . Multidisciplinary Management: The variety of abnormalities present in FA prompts recommendations for optimal oral health care to prevent head and neck squamous cell carcinoma (HNSCC). Also included in this team is gynecology and infertility, dermatology, gastroenterology, endocrinology, otology, and audiology. Discovery of these skeletal anomalies commonly precede the diagnosis of FA: • Underdeveloped, missing, or duplicated thumb,

Figure 1 . Right arm pictured: hypoplasia of the radii with concave bowing of the ulna and radial deviation (club hands). Thumb aplasia present (not pictured).

- Patient most likely does not have FA; (unless strong clinical evidence, then fibroblast testing should be performed to rule out somatic mocasism)

Test 1: Chromosomal Breakage Test (gold standard) +

Test 2: Targeted Gene Panel (23 genes) by next generation sequencing + Deletion/Duplication testing

Figure 2 . Right arm pictured: centralization procedure of the right wrist on the ulna. Thumb aplasia pictured.

Patient Case If negative, a whole genome sequence is recommended

If positive, diagnosis of FA can be made and detection of pathogenic mutations in FA genes

A 15 month old male presented to the pediatric office for a routine check up for which his weight, height and head circumference has trended less than or equal to the third percentile. During this visit, the patient showed appropriate motor function of the hand following a centralization procedure of the right wrist two months prior. Past medical history includes hyperbilirubinemia, hypoglycemia, small for gestational age, and mild penoscrotal web. Multiple unique fetal anomalies during his prenatal screening: • bilateral radius anomalies • bilateral hand malformations and malrotations • single umbilical artery • aberrant ductus venosus • mild bilateral ventriculomegaly • cerebellar hypoplasia. At four days old, the patient’s bilirubin levels reached 15.3 mg/dL (reference range is <12 mg/dL). These highly critical bilirubin levels prompted phototherapy. During this time a CBC with differential was ordered and the following was discovered: • low RBC count, low hematocrit, low hemoglobin (>8 g/dL), The patient’s parents were screened for Fanconi anemia and both were found to be carriers. The multiple anatomic abnormalities prompted VACTERL-H screening. The positive screening in both parents and laboratory CBC work up warranted diagnostic testing. The chromosomal breakage test using DEB and MMC was positive. The positive breakage test suggested genomic testing in which homozygous mutations in FANCG were detected. At nine months age, the patient was seen by a pediatric orthopedic surgeon where AP and lateral radiographs of the bilateral forearms demonstrated hypoplasia of the radii with concave bowing of the ulna and bilateral radial deviation, more commonly described as club hands. In addition, thumb aplasia and shortened forearms were present.At 13 months of age, the patient underwent centralization procedure of the right wrist on the ulna, diagnostic bone marrow aspiration and biopsies. During the procedure, the patient’s wrist was moved to the central part of the distal ulna with the goal to correct the radial deviation. Furthermore, the application of a long arm cast was done. At the three week post operative follow-up, the focused exam of the right upper extremity showed well perfusion of the hand with brisk capillary refill, palpable radial pulse, no evidence of infection, and independent movement of all digits. The cast was removed and the arm was placed in a custom thermoplastic splint. Four weeks later, the patient returned to the clinic to discuss an eventual thumb pollicization procedure. • significantly low neutrophil count (<1,500/mm 3 ), • significantly high platelet count (>150,000). • ovalocytes, macrocytosis, giant platelets, poikilocytes, and polychromasia.

• Shortened or missing radius, • Shortened, curved forearm,

• A hand that develops perpendicularly to the forearm, • Impaired movement in the wrist, fingers, and elbow.

Table 1 . Severity of bone marrow failure classification 1

Mild

Moderate (hypoplastic or aplastic anemia)

Severe (or severe aplastic anemia)

The majority of the skeletal features above were present in our 15 month male, and his absent thumb is classified under the Type V deficiency shown in Table 2. Treatment of patients with radial club hands and absent thumbs include centralization and pollicization surgery, using the second or third metacarpal bones and tendon transfer 4 . Early referral to an orthopedic upper extremity specialist increases functional ability of the arm and thumb as well as its cosmetic outcomes.The recommendation to perform these procedures at a young age is supported by a child’s ability to optimize brain plasticity and capability to incorporate their hand functionality into their daily activities 5 . Complications of the centralization procedure: high rate of recurrence of deformity, wrist stiffness, and damage of the ulnar physis also known as the growth plate. Complications of pollicization procedures include first web space contracture, lack of opposition, malrotation, excessive length, and stiffness 5 .

Hemoglobin (Hb) level

≥ 8 g/dL

<8 g/dL

<8 g/dL

Absolute neutrophil count (ANC)

<1,500/mm 3

<1,000/mm 3

<500/mm 3

Platelet count

150,000-50,000/mm 3

<50,000/mm 3

<30,000/mm 3

References

Table 2. Thumb deficiency classification and treatment paradigm 1

Type

Findings

Treatment

1. Sroka, I. (2014). Clinical care guidelines . Fanconi Anemia Research Fund. https://www.fanconi.org/explore/clinical-care-guidelines 2. Deaconu, A., Vodă, D., & Bulucea, D. (2014). Fanconi anemia — case report of rare aplastic anemia at child. Acta Medica Marisiensis , 60 (3), 125– 128. https://doi.org/10.2478/amma-2014-0027 3. Bhandari, J. (2022, August). Fanconi anemia . National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK559133/ 4. Lahiji, F. A., Asgari, F., Mirzaee, F., Zafarani, Z., & Aslani, H. (2019). Clinical and functional results of radial club hand with centralization and pollicization using the second metacarpus: A clinical case series. International Journal of Surgery Case Reports , 61 , 285– 290. https://doi.org/10.1016/j.ijscr.2019.07.076 5. Kozin, S. H. (2012). Pollicization: The concept, technical details, and outcome. Clinics in Orthopedic Surgery , 4 (1), 18. https://doi.org/10.4055/cios.2012.4.1.18 Acknowledgements

I

Minor generalized hypoplasia Absence of intrinsic thenar muscles First web space narrowing Ulnar collateral ligament insufficiency

No treatment

II

Opponensplasty First web release UCL reconstruction

III

Similar findings in type II + Extrinsic muscle and tendon abdnormalities Skeletal deficiency Stable carpometacarpal (CMC) joint (subtype IIIA) Unstable CMC joint (subtype IIIB)

Reconstruction (for subtype IIIA) Pollicization (for subtype IIIB)

IV

Floating thumb Absent thumb

Pollicization Pollicization

V

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