Familial Cyclic Vomiting Syndrome

Abstract

A family is described in which four members suffer from cycling vomiting syndrome (CVS), without additional symptoms. So far, only a few CVS families have been described in literature, and most patients belonging to these families had other symptoms in addition to CVS. We conclude that ‘pure’ CVS may also be a hereditary disorder. Its relation to migraine will be discussed.

Introduction

Cyclic vomiting syndrome (CVS) is characterized by recurrent, explosive bouts of vomiting punctuating periods of normal health (1–3). The episodes are stereotypical within individuals, with a rapid onset, most often during the night or early morning, a high peak frequency of vomiting every 10–15 min, associated with nausea, retching, abdominal pain, lethargy, anorexia, pallor, and a rapid resolution to completely normal. Median age of onset is five years, and median age of resolution of symptoms at the age of 10.

The cause of CVS is unknown. Many possibilities have been suggested, including neurogenic, mitochondrial, hormonal, cardiovascular and gastrointestinal factors (3). Familial occurrence of CVS has not been described often, and therefore genetic causes of CVS have not received much attention. Here, we describe a three-generation family in which four patients suffer from CVS, albeit with a later age at onset than usual.

The family

The family pedigree is depicted in Fig. 1. Information on the proband (III-2), her daughter (IV-1), and her mother (II-3) was obtained by a direct interview. Information on the remaining family members of generation I and II was obtained through II-3.

Figure 1

Pedigree of the family. ▪,□ males; •,○ females; •,▪ individuals with attacks of vomiting. Arabic number within symbols indicate the number of inidviduals, the arrow points to the index case, strikethrough indicates deceased persons.

III-2

The proband, a 41-year-old-woman, remembered suffering from car sickness in her youth. In addition, she often had to stay at home during holidays because of physical complaints. From the age of 15 she experienced attacks of vomiting. These attacks typically start in the morning, after waking up with a wretched feeling and cold hands and feet. She feels increasingly nauseated, yawns frequently and has to stay in the dark because of photophobia. Shortly thereafter, explosive and severe vomiting starts, lasting one or two days. The vomiting is accompanied by lacrimation, rhinorrhoea, diarrhoea and a feeling of apathy, she does not have headache, abdominal pain, fever, or dizziness. After each bout of vomiting the feeling of nausea decreases, but returns after a short period. The number of vomits varies between four per hour to a total of six during the whole attack. The frequency of the attacks varied between two and four per month. Attacks often occur on the first or second day of the menstrual period, but also outside this period (and not specifically in the second half of the menstrual cycle). Stress can trigger the attacks. During the two pregnancies, attacks continued to occur in the first trimester, but completely disappeared in the second and third trimester. Admission to a hospital because of dehydration has never been necessary. In 90% of the episodes, her husband noted a ‘peculiar smell of breath’, shortly before the attack started. The patient herself mentioned increased appetite and fluid retention as premonitory symptoms. The patient never experienced temporarily visual disturbances or other focal neurological symptoms accompanying the attacks.

Extensive internal, gynaecological and neurological work-up revealed no abnormalities, as were extensive laboratory investigations and screening for various metabolic diseases, including fasting lactate and pyruvate. Treatment with anti-emetics resulted in a slight decrease of nausea and number of vomits during the attacks. According to the patient, sumatriptan and zolmitriptan delayed the onset of the attacks, but did not abort them. Recently, the attacks completely disappeared after starting pizotifen 1.5 mg daily, but this medication was stopped by the patient, as she gained 5 kg of weight within a month, and moreover, the attacks re-occurred.

IV-1

Since the age of 13, the daughter of the proband (born in 1986) has suffered from monthly attacks of severe malaise and abdominal pain accompanied by pallor and sweating, mostly occurring on the first day of menstruation. During the attacks, she had to go to bed, and severe bouts of vomiting occurred, sometimes with diarrhoea. She had no headache. The vomiting lasted for three to four hours, and after 12–24 h the patient had fully recovered. After she started to use a contraceptive in August 2001, the attacks have stopped. Standard medical examination by a general practitioner revealed no abnormalities. Further examination was not initiated or requested, as her mother recognized the symptoms of her daughter as identical to her own, and because the attacks had not recurred.

II-3

The mother of the proband (currently 74 years old) had two periods of admittance to the hospital in her twenties, because of a peritonitis and of a cholecystectomy because of recurrent vomiting, without success. She reported stereotypical attacks of severe nausea and vomiting starting at the age of 15.

Shortly before the onset of vomiting, she is sleepy and yawns constantly. She vomits approximately once per hour, is dizzy and sweaty and sensitive to light. She has no headache, abdominal pain, diarrhoea, or fever. The attacks can last one to three days, and can sometimes be shortened by sleep. The frequency of the attacks was two attacks per month, but became less frequent after menopause. There was no relation between the attacks and menstruation, and the attacks did not disappear during her two pregnancies.

She remembered that when she was a child, her elder brother (II-1; deceased) had monthly attacks of vomiting without headache, for which he ‘very often stood vomiting in the back of the garden’. These attacks lasted approximately one day.

One of her sisters suffered from attacks of headache, without nausea, vomiting, photophobia or phonophobia. The remaining six siblings had no attacks of vomiting, nor migraine. The grandmother of the proband (I-2) suffered from chronic daily headache without vomiting, for which she often took aspirin and went to bed each afternoon.

Discussion

Here we report a family in which four subjects (three females and one male) suffer from a stereotypical syndrome of episodic vomiting, without headache. The symptoms of those patients that were interviewed personally (II-1, III-1 and IV-1) fulfilled the criteria of CVS (3). However, the attacks started between the age of 13 and 15. Although CVS may start from infancy to mature adulthood (4, 5), the median age at onset is 5.2 years (3). This prompted us to consider alternative diagnoses.

Age at onset around menarche, association with menstruation, and a decrease in attack frequency during pregancy (III-2) or by the use of a contraceptive pill (IV-1) suggest a premenstrual syndrome rather than CVS. Yet, the attacks were not restricted to the second half of the menstrual cycle (II-3 and III-2), and also occurred in a male member of the family (II-1). Besides, explosive vomiting is not a part of the premenstrual syndrome, and menstruation is a well-known triggerfactor for CVS (3, 6).

Abdominal migraine is a ‘heterogenous, undefined disorder, without markers’, with age at onset in childhood (7). Clinical comparison could hardly distinguish this syndrome from CVS (3, 8). In abdominal migraine, the predominant symptom is abdominal pain while in CVS it is the vomiting. In the family described here, only subject IV-1 actually complained of abdominal pain.

Hereditary metabolic diseases can be the underlying disorder of recurrent vomiting, such as an amino-acid disorder, organic acidaemia, fatty acid oxidation defect, disorder of gluconeogenesis, hereditary fructose intolerance or porphyria (9) Such disorder was highly unlikely, as none of the patients had any other symptoms in association with CVS, even after many years of disease duration, and many of the metabolic disorders were excluded by laboratory tests in the proband.

Based on the arguments mentioned above, we consider it most likely that the patients in our family suffer from CVS. To the best of our knowledge, only one publication exists which describes familial occurrence of CVS. Boles and Williams (10) reported on signs of mitochondrial inheritance in six CVS patients and their families. In family 1, CVS was present in the index case, and at least one other family member. Both had no additional findings, and, interestingly, in the uncle of the index case, the attacks started at the age of 25. In family 4, both the index case and the mother were diagnosed as having CVS, but several family members have additional findings. Mitochondrial DNA was studied for mutations and a large mitochondrial DNA rearrangement was found in the index case of family 3, a patient with additional mental retardation and seizures. No changes in DNA were found in the remaining families. Interestingly, elevated body fluid lactate was found in five out of six index cases.

In the pedigree described in our study, the maternal inheritance pattern suggests a mitochondrial disorder. However, lactate and pyruvate were normal in the index case, and none of the family members with CVS had additional symptoms or signs typical for mitochondrial dysfunction, such as short stature, learning disability, or epilepsy.

A clinical relation between CVS and migraine has been suggested repeatedly: up to 40% of patients with CVS have headache during the attacks, and in 27% of cases CVS progresses to migraine in adulthood. Furthermore, 82% of the patients have a positive family history of migraine (3, 6, 11). Migraine has a strong genetic contribution, and the association of several chromosomal loci with migraine has been demonstrated (12). Migraine-associated mutations have been found in only one gene so far, the CACNA1A calcium-channel gene on chromosome 19p (13). It has been suggested that this gene must be considered an ‘aura-gene’, as mutations have been found in patients with familial hemiplegic migraine, a severe subtype of migraine with aura (7), and it has been shown that the CACNA1A gene region contributes more to migraine with aura than to migraine without aura (14, 15). The CVS family described here suggests the existence of a ‘vomiting-gene’, which could theoretically also play a role in migraine.