Introduction

Anorexia Nervosa (AN) is a chronic illness with serious physical complications, including hormonal and neuroendocrine damages, and often psychiatric co-morbidities [1, 2]. The main characteristics of the disease are a restriction of energy intake that leads to low body weight, the fear of becoming fat and disturbed body image [1, 2]. The disease commonly appears during adolescence, mostly among girls; therefore, puberty can be delayed [1,2,3]. AN has the highest mortality rate among all psychiatric disorders. The lifetime prevalence among females suffering from AN is between 0.6 and 2.2% [1, 2].

The amenorrhea criteria were part of the diagnosis of AN in the Diagnostic and Statistical Manual of Mental Disorder—4th Edition (DSM IV) but not in the DSM-V as amenorrhea is not observed in men nor in women on contraception, in pre- or post-menarchal females [4]. In addition, the clinical characteristics and course of the disease of females suffering from AN are similar whether they have amenorrhea or not [1, 2, 5].

As AN onset in childhood delays the development of normal puberty, it is often considered that the absence of menstruation is a consequence of AN, which is referred to as functional hypogonadotropic hypogonadism [6, 7]. Delayed puberty (DP) is defined by the absence of physical signs of puberty 2–2.5 standard deviations above the mean age and affects approximately 2% of adolescents [3, 6, 7]. In Caucasian girls, it is referred to as an absence of thelarche by age 13 years, more than 5 years between breast buds and menarche, or more than 16 years of age for spontaneous menarche [7].

The diagnostic challenge appears when the DP is both functional and congenital. Included in the differential diagnostic of DP is congenital hypogonadotropic hypogonadism. Kallmann syndrome (KS) is a rare Congenital Hypogonadotropic Hypogonadism (CHH) due to a failure of GnRH secretion [3, 7, 8]. Diagnosis is based on hypogonadotropic hypogonadism with hypo- or anosmia [3, 7, 8]. The prevalence of KS in females is 1:125,000 and is more frequent among males [8]. Thanks to the genetic research of these last decades, more recent studies suggest that the diagnosis of CHH is understated [7]. In females, DP including primary amenorrhea, low blood levels of sex hormones, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), combined with poor sense of smell can lead to the diagnosis of KS [3, 7].

The diagnosis of CHH is challenging during childhood and adolescence especially when AN mimics its consequences. Due to DP in early onset AN, the follow-up must be rigorous and should include the entire congenital aspect.

Case presentation

In June 2018, the patient was 12 years old and had been hospitalised since March 2018 in a Pediatric Department, for restricted food intake. She consumed no more than 300 cal per day and practiced 7.5 h of athletics per week. The patient had no purging behaviours and reduced her liquid intake. She claimed that she was afraid to gain weight, to become fat and to develop secondary sexual characteristics. Her previous weight corresponded to the 25th percentile and dropped rapidly below the 1st percentile (BMI 12 kg/cm2). According to the DSM-V, all these criteria lead to a diagnosis of AN. No other psychiatric disorder diagnosis was made.

According to her medical history, she had a forearm fracture when she was 8 years old and in 2015 an MRI indicated an idiopathic absence of the olfactory bulb (Fig. 1). No pubertal signs were observed, including menarche. There was no family history of eating disorder or other psychiatric disease, nor somatic illness. Nothing was reported concerning her development.

Fig. 1
figure 1

Patient’s coronal brain MRI in 2015. The arrow points to the agenesia of the olfactory bulb

Full size image

The clinical examination revealed a bradycardia (50 bpm), a low blood pressure (80/50 mmHg), an acrocyanosis, severe chills, rough skin, and lanugo. Blood tests detected an acute prerenal failure and low level of serum platelets (174.000/µL). During this indwelling, an aortic bicuspid was discovered thanks to complementary exams. A nasogastric tube was then placed to correct the state of severe malnutrition.

In July 2018, she was transferred to an academic outpatient psychiatric hospital where she stayed for 3 and a half months. Subsequently, she was treated as an outpatient by a dietician, a psychologist and a pediatrician for several months.

Due to a lack of compliance and a lack of improvement both psychologically and physically, she was admitted in April 2019 to another inpatient academic hospital in the Adolescent Psychiatric Department. Again, she had diminished her dietary intake and was practicing physical activity at home. The aim of this stay was to implement a multidisciplinary treatment approach including individual and standard family therapy as well as individual caring. Physical activities were forbidden, and she was compelled to rest 2 h after each meal. The refeeding program was established by a dietician with a decreasing intake of nasogastric tube, as her oral food intake increased. Her mental status examination showed no anhedonia, no abulia and no suicidal thought. Her mood state was low, irritable, with rumination, severe anxiety, constant thought about food and desire to control all food intake. Promptly, to overcome these symptoms, a pharmacological therapy which included antidepressant and atypical neuroleptic medications was initiated. She was hospitalised to this department 3 times between April 2019 and June 2020, each time for multiple months.

During each stay, all routine complementary exams were performed, such as electrocardiogram and electroencephalogram, which were normal every time. A bone mineral density scan done in April 2019 was normal (Z-Score on the femoral collar − 1.3). The bone gamma scan done at the same time was within the limits of the standard for her age. The first record of LH and FSH in her blood test was in September 2019, when she 13 years old, revealing < 1 UI/l (normal range: 1.8–11.8 UI/L) and 3.7 UI/l (normal range:3.0–8.1 UI/L), respectively. She had not yet reached menarche. At that time, it was assumed that her low levels of gonadotropins hormones and the primary amenorrhea were due to her AN.

Despite her multiple hospitalisations and refeeding attempts, the patient continued to lose weight. As soon as she was discharged from the inpatient hospital, she returned to her restricting behaviours.

In January 2020, she was almost 15 years old and had an appointment in an outpatient clinic practicing Family-Based Treatment for AN. The patient had the phenotype of a prepubertal teenager, and no external signs of pubertal characteristic were observed (Tanner stage below 1 for all parts). A complete medical history was collected and brought up the absence of olfactory bulb. We prescribed a new blood test including her gonadotropic values. FSH and LH were below the threshold, 0.2 UI/L (normal range: 3.0–8.1 UI/L) and < 0.1UI/L (normal range: 1.8–11.8 UI/L), respectively. Estradiol levels were < 21 ng/L (normal range: 21–251 ng/L) and progesterone levels < 0.5 µg/L (normal range: < 0.3 µg/L). These blood results combined with DP and the absence of an olfactory bulb conducted to the diagnosis of KS.

We prescribed a bone age study which indicated bone age was above 12 years old. We continued treatment according to the Family-Based Therapy model and in parallel, referred the patient to multidisciplinary care for genetic counselling and endocrine management. She started taking estradiol 0.2 mg per day and gradually increased the doses which improved weight gain in 4 months, started the thelarche and provoked vaginal discharge.

Discussion

Since most organ function damage occurs during the acute phase of AN, early diagnosis is needed to prevent long-term complications and death [1]. AN comprises psychological impairment and restrictive cognitive behaviours resulting in somatic co-morbidities due to low weight and poor nutrition that involve almost all organs [1, 2]. A direct consequence of starvation is death while indirect causes of mortality, including suicide, occurs in 20% of all AN deaths [1, 2]. The younger the patient, the more severe the prognosis is. Nevertheless, the earlier the diagnosis is made, the better the prognosis is [2]. During childhood, the body and the brain are still maturing, and numerous endocrine changes occur [6]. Childhood onset of AN is considered when it begins before 14 years of age [6]. This pre-teenage period is fragile and crucial as endocrine disturbances might have more significant impacts than during adolescence [6]. Typical complications for AN children are low body weight and growth and DP, especially when the disease manifests before menarche [6]. In light of all the possible consequences of AN, a particular follow-up must be ensured to prevent growth retardation, future fertility problems and osteoporosis which represent long-term sequelae of the disease [1]. The earlier nutritional restoration is initiated, the better the prognosis will be for mid- and long-term complications [1, 6]. This basic treatment is undertaken with a multidisciplinary in- or outpatient team and allows to improve somatic conditions [1]

The patient would never have had natural menarche as her hypothalamic–pituitary–gonadal axis was aberrant. Her primary amenorrhea and low hypogonadotropic serum levels were due to her CHH. Since AN can mask symptoms of other diseases or syndromes, AN can lead to broader consequences than expected.

To measure the consequence of AN and to circumvent misdiagnosis such as KS, an in-depth medical history including a psychiatric evaluation, blood and biochemical tests, ECG and a full physical assessment are to be performed [2]. CHH includes other peculiarities, such as renal agenesis, synkinesis, eye movement disorders, sensorineural hearing loss, midline brain defects (e.g., absence of the corpus callosum or cleft lip/palate), dental agenesis, skeletal defects, bone abnormalities, and cardiovascular defects. These should be investigated when a patient presents a DP. KS is associated with anosmia, a lack of sense of smell, explained by a link, in the foetal development, between GnRh and the olfactory placode [7, 8].

This clinical case encompasses both functional and congenital hypogonadism. When prepubertal AN presents, hypogonadism is a differential diagnostic that should be investigated. Furthermore, absence of puberty onset (thelarche, growth spurt, pubic hair growth and finally menarche) for so many years is an alarming sign. Only 40% of CHH are explained by genetic mutation which is why a proper and complete case history is key and requisite for each AN patient [8]. A physical examination, blood tests analysis and the screening of olfactory function are to be done. Once a KS diagnosis is suspected, genetic counselling and testing are propounded [7, 8]. A recent genome-wide association study (GWAS) reported eight significant loci in AN which suggests considering AN as a psychiatric and a metabolic disorder [9]. Links between AN and other diseases (autoimmune and/or genetic) have currently become material in the field of research and could be considered in our case.

The suggested treatment for KS is to provide estrogen replacement therapy. The aim is to mimic the pubertal estrogen effects to prevent the consequences of the lack of this hormone including the risk of stunted growth and low bone mineral density which is similarly recommended in AN to improve and prevent long-term osteoporosis [1, 2, 6,7,8]. Additionally, this treatment is used to treat infertility and gives the patient the opportunity to later have children [7].

Our patient’s prognosis was poor as she had been noncompliant for a long time [1]. Intriguingly, after the announcement of the KS to the patient and family, the course of AN treatment positively evolved. The patient was more collaborative and seemed to be reassured as the diagnosis clarified the symptoms that had always been unexplained till then.

The main limit of our case is the scarcity of both diseases. The prevalence of KS is so low that it is nearly impossible to conduct studies on this syndrome with or without AN. Moreover, puberty congenital hypogonadism in adolescence is a diagnosis of exclusion, rendering the diagnosis of KS even more difficult [7]. More guidelines should be outlined to conduct a proper distinction to establish the origin of the DP.

What is already known on this subject?

To our knowledge, a single case dating from 1993 with AN and KS is reported [10]. This case is the second reported case in over 30 years. Poor prevalence of those diseases prevents from studying correlations although it should be performed.

What does this study add?

This study shows the importance of targeted medical history and adds the suggestion to perform a systematic follow-up of prepubertal AN with DP. Similar cases have not yet been detected. This case invites us to be more careful about the possible association between those diseases.

Conclusion

In our daily practice, we always try to point out a single disease explaining all the symptoms observed. It is crucial to remember that another disease could be associated. This case teaches us the need of being more diligent when taking the medical history of our patients, especially with AN which has serious mid- and long-term somatic consequences if not completely diagnosed and correctly treated. It is imperative to ensure a methodical work-up and follow-up concerning puberty with AN children to prevent misdiagnosis.