Fumarate Hydratase Deficiency

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of FH deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of FH is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect (multi)exon and whole-gene deletions or duplications.
• A seizure and/or neonatal encephalopathy multigene panel that includes FH and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and/or intellectual disability, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Fetal Manifestations

Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [Coughlin et al 1998, Maradin et al 2006, Allegri et al 2010, Saini & Singhi 2013]. Enlarged cerebral ventricles and other brain abnormalities have been identified by fetal ultrasound [Chan et al 2017].

Neonatal and Early-Infantile Encephalopathy

Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [Phillips et al 2006]. If symptoms are not apparent at birth, affected infants show severe neurologic abnormalities within age one week to one month, including poor feeding, failure to thrive, and hypotonia. These infants have poor eye contact and variable degrees of depressed consciousness including lethargy, stupor, and even coma. Head and neck control may be entirely absent. Infants gain weight slowly and may require tube feedings.

Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [Kerrigan et al 2000, Allegri et al 2010]. Infantile spasms accompanied by hypsarrhythmia on EEG have been reported [Remes et al 2004, Loeffen et al 2005]. Seizures are often resistant to treatment.

Dysmorphic Facial Features

Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [Allegri et al 2010]. Less frequent features (<50%) include cleft ala nasi or anteverted nares, ear anomalies, or narrow forehead [Allegri et al 2010].

Head Size

Head size has been reported as microcephalic in 36% of all affected individuals [Allegri et al 2010]. However, in one large kindred (8 affected individuals in 1 consanguineous family), 88% (7 of 8 affected individuals) were reported to have "relative macrocephaly," since head sizes were within the normal range, but in association with brain imaging findings of cerebral atrophy and mild communicating hydrocephalus (enlarged extra-axial CSF spaces) [Kerrigan et al 2000]. That is, most children with FH deficiency appear have abnormally limited brain growth.

Brain Imaging Findings

The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by Allegri et al [2010]), or ventriculomegaly (82% of all individuals summarized by Allegri et al [2010]). Brain volume loss (or more likely lack of brain volume development) can be accompanied by a relative decrease in CSF reabsorption, leading to a normal head size with a small brain but modestly expanded CSF compartments. In the series of Kerrigan et al [2000], two such individuals were shunted for possible "hydrocephalus" leading to collapse of the CSF compartments and secondary microcephaly without clinical improvement.

Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [Phillips et al 2006], deficient closure of the Sylvian opercula [Kerrigan et al 2000, Phillips et al 2006], and a hypoplastic brain stem [Kerrigan et al 2000, Phillips et al 2006, Tregoning et al 2013]. Abnormalities of the corpus callosum are also reported, including thinning [Maradin et al 2006, Phillips et al 2006] and absence [Coughlin et al 1998]. Hyperintense basal ganglia lesions in the caudate and thalamic nuclei, and elevated lactate on MRS have also been reported [Tregoning et al 2013]. Diffuse bilateral polymicrogyria of the cerebral cortex has also been reported, a universal feature in the eight affected individuals from one kindred reported by Kerrigan et al [2000] but also noted in three additional unrelated individuals [Zeng et al 2006, Ottolenghi et al 2011].

Acute Metabolic Derangements

Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in individuals with FH deficiency [Allegri et al 2010, Saini & Singhi 2013, Baştuğ et al 2014].

Other Clinical Features

Other findings can include neonatal polycythemia [Kerrigan et al 2000], recurrent neutropenia [Tregoning et al 2013, Guitart et al 2017], recurrent vomiting with hepatosplenomegaly [Allegri et al 2010, Tregoning et al 2013], and pancreatitis [Phillips et al 2006]. Visual disturbances and optic nerve hypoplasia were described in two families [Kerrigan et al 2000, Saini & Singhi 2013]. Birth defects involving other organ systems are uncommon.

Clinical Course

The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [Loeffen et al 2005]. Many children are unable to feed successfully, with failure to gain weight and increased risk for aspiration. Accordingly, feedings administered through gastrostomy tube may be required.

Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.

However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [Ottolenghi et al 2011]. Consequently, counseling of families with children with FH deficiency should include recognition of the range of severity.

Heterozygotes

Most heterozygous parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [Tomlinson et al 2002], a report of a mother with uterine myomas [Maradin et al 2006], the death of the mother of an affected child from "renal cell carcinoma" in a third family [VE Shih, unpublished], and the detection of renal carcinoma in an asymptomatic obligate heterozygous female raise the possibility of increased risk for HLRCC in the heterozygous relatives of children with FH deficiency (see Hereditary Leiomyomatosis with Renal Cell Cancer).